Benzamide mGluR5 positive allosteric modulators and methods of making and using same

ABSTRACT

In one aspect, the invention relates to compounds, including phenylethynylbenzamide derivatives, cycloalkylethynylbenzamide derivatives, styrylbenzamide derivatives, 4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzamide derivatives, 4-(pyridinylethynyl)benzamide derivatives, and N 1 -phenylterephthalamide derivatives, which are useful as positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 60/941,686,filed Jun. 3, 2007, which is hereby incorporated herein by reference inits entirety.

ACKNOWLEDGMENT

This invention was made with government support under Grants NIH/NIMHR01 MH062646 and F32 NS049865 awarded by the National Institutes ofHealth. The United States government has certain rights in theinvention.

BACKGROUND

L-glutamic acid, the most commonly occurring neurotransmitter in thecentral nervous system, plays a role in a large number of physiologicalprocesses. The glutamate-dependent stimulus receptors are divided intotwo main groups. The first main group forms ligand-controlled ionchannels. The second main group is metabotropic glutamate receptors(mGluRs), which belong to the family of G-protein-coupled receptors.Metabotropic glutamate receptors, including mGluR5, have been implicatedin a wide range of biological functions, indicating a potential role forthe mGluR5 receptor in a variety of disease processes in mammals.Ligands of metabotropic glutamate receptors can be used for thetreatment or prevention of acute and/or chronic neurological and/orpsychiatric disorders associated with glutamate dysfunction, such aspsychosis, schizophrenia, age-related cognitive decline, and the like.

Selective positive allosteric modulators are compounds that do notdirectly activate receptors by themselves, but binding of thesecompounds increase the affinity of a glutamate-site agonist at itsextracellular N-terminal binding site. Positive allosteric modulation(potentiations) is thus an attractive mechanism for enhancingappropriate physiological receptor activation.

Unfortunately, there is a scarcity of selective positive allostericmodulators for the mGluR5 receptor. Further, conventional mGluR5receptor modulators typically lack satisfactory aqueous solubility andexhibit poor oral bioavailability. Therefore, there remains a need formethods and compositions that overcome these deficiencies and thateffectively provide selective positive allosteric modulators for themGluR5 receptor.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tocompounds useful as positive allosteric modulators (i.e., potentiators)of the metabotropic glutamate receptor subtype 5 (mGluR5), methods ofmaking same, pharmaceutical compositions comprising same, and methods oftreating neurological and psychiatric disorders associated withglutamate dysfunction using same.

Disclosed are compounds having a structure represented by a formula:

wherein R¹ and R² are independently optionally substituted organicradicals comprising from 1 to 12 carbon atoms; wherein each

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; whereinZ¹, Z², and Z³ are independently selected from N and C—R⁴, with theproviso that no more than two of Z¹, Z², and Z³ are nitrogen; andwherein R⁴ comprises up to five substituents independently selected fromhydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substitutedalkyl or alkenyl or alkynyl, optionally substituted heteroalkyl orheteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl orcycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; or a pharmaceutically acceptable salt orN-oxide thereof, wherein the compound exhibits potentiation of mGluR5response to glutamate as an increase in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith rat mGluR5 in the presence of the compound, compared to theresponse to glutamate in the absence of the compound.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ and R² are independently hydrogen or an optionallysubstituted organic radical comprising from 1 to 12 carbon atoms;wherein each

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; whereinZ¹, Z², and Z³ are independently selected from N and C—R⁴, with theproviso that no more than two of Z¹, Z², and Z³ are nitrogen; wherein R⁴comprises up to five substituents independently selected from hydrogen,halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; and wherein R^(7a) and R^(7b) together form anoptionally substituted carbocyclic or heterocyclic ring having from twoto five carbons or are independently selected from hydrogen, halogen,hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising1 to 5 carbon atoms selected from optionally substituted C1-C6 alkyl orC2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkylor C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substitutedC3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionallysubstituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8heterocycloalkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkoxyl, optionally substitutedthioalkyl, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, and optionally substituted amino, thioamido,amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, andalkylamine-carbonyl; or a pharmaceutically acceptable salt or N-oxidethereof, wherein the compound exhibits potentiation of mGluR5 responseto glutamate as an increase in response to non-maximal concentrations ofglutamate in human embryonic kidney cells transfected with rat mGluR5 inthe presence of the compound, compared to the response to glutamate inthe absence of the compound.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ and R² are independently optionally substituted organicradicals comprising from 1 to 12 carbon atoms; wherein each

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; whereinZ¹, Z², and Z³ are independently selected from N and C—R⁴, with theproviso that no more than two of Z¹, Z², and Z³ are nitrogen; andwherein R⁴ comprises up to five substituents independently selected fromhydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substitutedalkyl or alkenyl or alkynyl, optionally substituted heteroalkyl orheteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl orcycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; or a pharmaceutically acceptable salt orN-oxide thereof, wherein the compound exhibits potentiation of mGluR5response to glutamate as an increase in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith rat mGluR5 in the presence of the compound, compared to theresponse to glutamate in the absence of the compound.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ and R² are independently hydrogen or an optionallysubstituted organic radical comprising from 1 to 12 carbon atoms;wherein each

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; whereinZ¹, Z², and Z³ are independently selected from N and C—R⁴, with theproviso that no more than two of Z¹, Z², and Z³ are nitrogen; wherein R⁴comprises up to five substituents independently selected from hydrogen,halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; and wherein R⁸ is selected from hydrogen andlower alkyl; or a pharmaceutically acceptable salt or N-oxide thereof,wherein the compound exhibits potentiation of mGluR5 response toglutamate as an increase in response to non-maximal concentrations ofglutamate in human embryonic kidney cells transfected with rat mGluR5 inthe presence of the compound, compared to the response to glutamate inthe absence of the compound.

Also disclosed are methods for the treatment of a neurological and/orpsychiatric disorder associated with glutamate dysfunction in a mammalcomprising the step of administering to the mammal at least one compoundhaving a structure represented by a formula:

wherein

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R¹and R² are independently hydrogen or an optionally substituted organicradical comprising from 1 to 12 carbon atoms; wherein R⁰ is anoptionally substituted organic radical comprising 4 to 14 carbon atoms,wherein L is an organic divalent radical comprising 1 to 7 carbon atomsand is selected from:

wherein R^(7a) and R^(7b) together form an optionally substitutedcarbocyclic or heterocyclic ring having from two to five carbons or areindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, amino, and an organic radical comprising 1 to 5 carbon atomsselected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl orC2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; and wherein R⁸ is selected from hydrogen, andan organic radical comprising 1 to 6 carbon atoms selected fromoptionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl,optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl,optionally substituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt or N-oxide thereof, in a dosage andamount effective to treat the neurological and/or psychiatric disorderassociated with glutamate dysfunction in the mammal.

Also disclosed are methods for potentiation of metabotropic glutamatereceptor activity in a mammal comprising the step of administering tothe mammal at least one compound having a structure represented by aformula:

wherein

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R¹and R² are independently hydrogen or an optionally substituted organicradical comprising from 1 to 12 carbon atoms; wherein R⁰ is anoptionally substituted organic radical comprising 4 to 14 carbon atoms;and wherein L is an organic divalent radical comprising 1 to 7 carbonatoms and is selected from:

wherein R^(7a) and R^(7b) together form an optionally substitutedcarbocyclic or heterocyclic ring having from two to five carbons or areindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, amino, and an organic radical comprising 1 to 5 carbon atomsselected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl orC2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; or a pharmaceutically acceptable salt orN-oxide thereof, in a dosage and amount effective to potentiatemetabotropic glutamate receptor activity in the mammal.

Also disclosed are methods for partial agonism of metabotropic glutamatereceptor activity in a mammal comprising the step of administering tothe mammal at least one compound having a structure represented by aformula:

wherein each

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R¹and R² are independently hydrogen or an optionally substituted organicradical comprising from 1 to 12 carbon atoms; wherein R⁰ is anoptionally substituted organic radical comprising 4 to 14 carbon atoms,wherein L is an organic divalent radical comprising 1 to 7 carbon atomsand is selected from:

wherein R^(7a) and R^(7b) together form an optionally substitutedcarbocyclic or heterocyclic ring having from two to five carbons or areindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, amino, and an organic radical comprising 1 to 5 carbon atomsselected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl orC2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; and or a pharmaceutically acceptable salt orN-oxide thereof, in a dosage and amount effective to exhibit partialagonism of metabotropic glutamate receptor activity in the mammal.

Also disclosed are methods for enhancing cognition in a mammalcomprising the step of administering to the mammal at least one compoundhaving a structure represented by a formula:

wherein each

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R¹and R² are independently hydrogen or an optionally substituted organicradical comprising from 1 to 12 carbon atoms; wherein R⁰ is anoptionally substituted organic radical comprising 4 to 14 carbon atoms,wherein L is an organic divalent radical comprising 1 to 7 carbon atomsand is selected from:

wherein R^(7a) and R^(7b) together form an optionally substitutedcarbocyclic or heterocyclic ring having from two to five carbons or areindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, amino, and an organic radical comprising 1 to 5 carbon atomsselected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl orC2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; and or a pharmaceutically acceptable salt orN-oxide thereof, in a dosage and amount effective to enhance cognitionin the mammal.

Also disclosed are methods for preparing a phenylethynylbenzamidederivative comprising the steps of coupling an arylacetylene with anaryl halide, wherein one of the arylacetylene or the aryl halide bears acarboxyl functionality; and forming an amide derivative of the carboxylfunctionality by reaction with an amine.

Also disclosed are methods for preparing a phenylethynylbenzamidederivative comprising the steps of coupling an arylacetylene with anaryl halide, wherein one of the arylacetylene or the aryl halide bears acarboxyl functionality; and forming an amide derivative of the carboxylfunctionality by reaction with an amine.

Also disclosed are methods for preparing a styrylbenzamide derivativecomprising the steps of coupling a styryl bornonic acid or a styrylboronic ester with an aryl halide, wherein one of the styryl bornonicacid or styryl boronic ester or the aryl halide bears a carboxylfunctionality; and forming an amide derivative of the carboxylfunctionality by reaction with an amine.

Also disclosed are methods for preparing a4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzamide derivative comprising thesteps of condensing an N′-hydroxybenzimidamide with an aryl carboxylicacid, wherein one of the N′-hydroxybenzimidamide or the aryl carboxylicacid bears an ester functionality; and forming an amide derivative ofthe ester functionality by reaction with an amine.

Also disclosed are methods for preparing a 4-(pyridinylethynyl)benzamidederivative comprising the steps of coupling an arylacetylene with anaryl halide, wherein one of the arylacetylene or the aryl halide bears acarboxyl functionality; and forming an amide derivative of the carboxylfunctionality by reaction with an amine.

Also disclosed are methods for preparing a N′-phenylterephthalamidederivative comprising the steps of reacting an aniline compound with abenzoic acid compound, wherein the benzoic acid compound bears acarboxyl functionality; and forming an amide derivative of the carboxylfunctionality by reaction with an amine.

Also disclosed are the products of the disclosed methods.

Also disclosed are pharmaceutical compositions comprising the disclosedcompounds. For example, the compositions can comprise a therapeuticallyeffective amount of one or more phenylethynylbenzamide derivatives,cycloalkylethynylbenzamide derivatives, styrylbenzamide derivatives,4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzamide derivatives,4-(pyridinylethynyl)benzamide derivatives, and/orN¹-phenylterephthalamide derivatives at least one phenylethynylbenzamidederivative and a pharmaceutically acceptable carrier.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying figures, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the invention.

FIG. 1 shows a schematic of the NMDA receptor.

FIG. 2 shows a schematic illustrating that activation of mGluR5potentiates NMDA receptor function.

FIG. 3 illustrates allosteric modulation of mGluR5.

FIG. 4 shows CDPPB as a potent and selective mGluR5 potentiator havingmodest efficacy in rodent behavioral models for antipsychoticicactivity.

FIG. 5 shows classification of compounds as agonists, potentiators, andantagonists.

FIG. 6 shows a schematic illustrating optimization of candidates.

FIG. 7 tabulates displacement of [3H]methoxyPEPy and shows binding tothe MPEP site with varying affinities.

FIG. 8 shows in vivo efficacy for(4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone (CompoundVU13).

FIG. 9 shows in vivo efficacy for(4-hydroxy-4-propylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone(Compound VU60).

FIG. 10 shows in vivo efficacy for(4-(hydroxymethyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone(Compound VU14/C104B2).

FIG. 11 shows cognitive improvement in a novel object recognition (NOR)paradigm by ADX47273.

FIG. 12 shows the chemical structures of mGluR5 PAMs with in vivoactivity in preclinical antipsychotic models.

FIG. 13 shows reversal of amphetamine-induced hyperlocomotion by CDPPBand ADX47273.

FIG. 14 shows reversal of amphetamine-induced hyperlocomotion byVU00013.

FIG. 15 shows reversal of amphetamine-induced prepulse inhibition (PPI)by CDPPB.

FIG. 16 shows reversal of amphetamine-induced prepulse inhibition (PPI)by ADX47273.

FIG. 17 shows the increase in strength of synaptic connections afterapplying a stimulus to the synapse in the absence and presence of twostructurally distinct mGluR5 PAMs, VU29 (top panel) and ADX47273 (bottompanel).

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

All publications mentioned herein are incorporated herein by referenceto disclose and describe the methods and/or materials in connection withwhich the publications are cited. The publications discussed herein areprovided solely for their disclosure prior to the filing date of thepresent application. Nothing herein is to be construed as an admissionthat the present invention is not entitled to antedate such publicationby virtue of prior invention. Further, the dates of publication providedherein can be different from the actual publication dates, which canneed to be independently confirmed.

A. DEFINITIONS

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. It is also understood that there are a number of valuesdisclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

A residue of a chemical species, as used in the specification andconcluding claims, refers to the moiety that is the resulting product ofthe chemical species in a particular reaction scheme or subsequentformulation or chemical product, regardless of whether the moiety isactually obtained from the chemical species. Thus, an ethylene glycolresidue in a polyester refers to one or more —OCH₂CH₂O— units in thepolyester, regardless of whether ethylene glycol was used to prepare thepolyester. Similarly, a sebacic acid residue in a polyester refers toone or more —CO(CH₂)₈CO— moieties in the polyester, regardless ofwhether the residue is obtained by reacting sebacic acid or an esterthereof to obtain the polyester.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or can not occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “mGluR5 receptor positive allosteric modulator”refers to any exogenously administered compound or agent that directlyor indirectly augments the activity of the mGluR5 receptor in thepresence or in the absence of the endogenous ligand (such as glutamate)in an animal, in particular a mammal, for example a human. The term“mGluR5 receptor positive allosteric modulator” includes a compound thatis an “mGluR5 receptor allosteric potentiator” or an “mGluR5 receptorallosteric agonist,” as well as a compound that has mixed activity asboth an “mGluR5 receptor allosteric potentiator” and an “mGluR5 receptorallosteric agonist.”

As used herein, the term “mGluR5 receptor allosteric potentiator” refersto any exogenously administered compound or agent that directly orindirectly augments the response produced by the endogenous ligand (suchas glutamate) when it binds to the orthosteric site of the mGluR5receptor in an animal, in particular a mammal, for example a human. ThemGluR5 receptor allosteric potentiator binds to a site other than theorthosteric site (an allosteric site) and positively augments theresponse of the receptor to an agonist. Because it does not inducedesensitization of the receptor, activity of a compound as an mGluR5receptor allosteric potentiator provides advantages over the use of apure mGluR5 receptor allosteric agonist. Such advantages can include,for example, increased safety margin, higher tolerability, diminishedpotential for abuse, and reduced toxicity.

As used herein, the term “mGluR5 receptor allosteric agonist” refers toany exogenously administered compound or agent that directly augmentsthe activity of the mGluR5 receptor in the absence of the endogenousligand (such as glutamate) in an animal, in particular a mammal, forexample a human. The mGluR5 receptor allosteric agonist binds to theorthosteric glutamate site of the mGluR5 receptor and directlyinfluences the orthosteric site of the mGluR5 receptor. Because it doesnot require the presence of the endogenous ligand, activity of acompound as an mGluR5 receptor allosteric agonist provides advantagesover the use of a pure mGluR5 receptor allosteric potentiator, such asmore rapid onset of action.

By “treatment” is meant the medical management of a patient with theintent to cure, ameliorate, stabilize, or prevent a disease,pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder.

By “prevent” or “preventing” is meant to preclude, avert, obviate,forestall, stop, or hinder something from happening, especially byadvance action. It is understood that where reduce, inhibit or preventare used herein, unless specifically indicated otherwise, the use of theother two words is also expressly disclosed.

As used herein, “diagnosed with a need for potentiation of metabotropicglutamate receptor activity” means having been subjected to a physicalexamination by a person of skill, for example, a physician, and found tohave a condition that can be diagnosed or treated by potentiation ofmetabotropic glutamate receptor activity. As used herein, “diagnosedwith a need for partial agonism of metabotropic glutamate receptoractivity” means having been subjected to a physical examination by aperson of skill, for example, a physician, and found to have a conditionthat can be diagnosed or treated by partial agonism of metabotropicglutamate receptor activity. As used herein, “diagnosed with a need fortreatment of one or more neurological and/or psychiatric disorderassociated with glutamate dysfunction” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have one or more neurological and/or psychiatric disorderassociated with glutamate dysfunction.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, and parenteral administration, including injectable suchas intravenous administration, intra-arterial administration,intramuscular administration, and subcutaneous administration.Administration can be continuous or intermittent. In various aspects, apreparation can be administered therapeutically; that is, administeredto treat an existing disease or condition. In further various aspects, apreparation can be administered prophylactically; that is, administeredfor prevention of a disease or condition.

As used herein, a “therapeutically effective amount” refers to an amountthat is sufficient to achieve the desired therapeutic result or to havean effect on undesired symptoms, but is generally insufficient to causeadverse side affects. The specific therapeutically effective dose levelfor any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the specific composition employed; the age, body weight, general health,sex and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of a compound at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved. If desired, the effective dailydose can be divided into multiple doses for purposes of administration.Consequently, single dose compositions can contain such amounts orsubmultiples thereof to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products. In further various aspects, a preparation canbe administered in a “prophylactically effective amount”; that is, anamount effective for prevention of a disease or condition.

As used herein, a “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity may be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions may also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms may be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form maybe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations may be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc.

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkylgroup can also be substituted or unsubstituted. The alkyl group can besubstituted with one or more groups including, but not limited to,optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide,hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A“lower alkyl” group is an alkyl group containing from one to six (e.g.,from one to four) carbon atoms.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” specifically refers to an alkyl group thatis substituted with one or more halide, e.g., fluorine, chlorine,bromine, or iodine. The term “alkoxyalkyl” specifically refers to analkyl group that is substituted with one or more alkoxy groups, asdescribed below. The term “alkylamino” specifically refers to an alkylgroup that is substituted with one or more amino groups, as describedbelow, and the like. When “alkyl” is used in one instance and a specificterm such as “alkylalcohol” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“alkylalcohol” and the like.

This practice is also used for other groups described herein. That is,while a term such as “cycloalkyl” refers to both unsubstituted andsubstituted cycloalkyl moieties, the substituted moieties can, inaddition, be specifically identified herein; for example, a particularsubstituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specificallyreferred to as, e.g., a “halogenated alkoxy,” a particular substitutedalkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, thepractice of using a general term, such as “cycloalkyl,” and a specificterm, such as “alkylcycloalkyl,” is not meant to imply that the generalterm does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is atype of cycloalkyl group as defined above, and is included within themeaning of the term “cycloalkyl,” where at least one of the carbon atomsof the ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. Thecycloalkyl group and heterocycloalkyl group can be substituted with oneor more groups including, but not limited to, optionally substitutedalkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl,sulfo-oxo, or thiol as described herein.

The term “polyalkylene group” as used herein is a group having two ormore CH₂ groups linked to one another. The polyalkylene group can berepresented by the formula —(CH₂)_(a)—, where “a” is an integer of from2 to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl orcycloalkyl group bonded through an ether linkage; that is, an “alkoxy”group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as definedabove. “Alkoxy” also includes polymers of alkoxy groups as justdescribed; that is, an alkoxy can be a polyether such as —OA¹-OA² or—OA¹-(OA²)_(a)-OA³, where “a” is an integer of from 1 to 200 and A¹, A²,and A³ are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino,carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro,silyl, sulfo-oxo, or thiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onecarbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,norbornenyl, and the like. The term “heterocycloalkenyl” is a type ofcycloalkenyl group as defined above, and is included within the meaningof the term “cycloalkenyl,” where at least one of the carbon atoms ofthe ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group andheterocycloalkenyl group can be substituted or unsubstituted. Thecycloalkenyl group and heterocycloalkenyl group can be substituted withone or more groups including, but not limited to, optionally substitutedalkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol asdescribed herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylicacid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl,sulfo-oxo, or thiol, as described herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-basedring composed of at least seven carbon atoms and containing at least onecarbon-carbon triple bound. Examples of cycloalkynyl groups include, butare not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and thelike. The term “heterocycloalkynyl” is a type of cycloalkenyl group asdefined above, and is included within the meaning of the term“cycloalkynyl,” where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, or phosphorus. The cycloalkynyl group andheterocycloalkynyl group can be substituted or unsubstituted. Thecycloalkynyl group and heterocycloalkynyl group can be substituted withone or more groups including, but not limited to, optionally substitutedalkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol asdescribed herein.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, phenoxybenzene, and the like. The term “aryl” alsoincludes “heteroaryl,” which is defined as a group that contains anaromatic group that has at least one heteroatom incorporated within thering of the aromatic group. Examples of heteroatoms include, but are notlimited to, nitrogen, oxygen, sulfur, and phosphorus. Likewise, the term“non-heteroaryl,” which is also included in the term “aryl,” defines agroup that contains an aromatic group that does not contain aheteroatom. The aryl group can be substituted or unsubstituted. The arylgroup can be substituted with one or more groups including, but notlimited to, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino,carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro,silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is aspecific type of aryl group and is included in the definition of “aryl.”Biaryl refers to two aryl groups that are bound together via a fusedring structure, as in naphthalene, or are attached via one or morecarbon-carbon bonds, as in biphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for acarbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by theformula NA¹A²A³, where A¹, A², and A³ can be, independently, hydrogen oroptionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be an optionally substituted alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “polyester” as usedherein is represented by the formula -(A¹O(O)C-A²-C(O)O)_(a)— or-(A¹O(O)C-A²-OC(O))_(a)—, where A¹ and A² can be, independently, anoptionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer from 1 to 500. “Polyester” is as the term used todescribe a group that is produced by the reaction between a compoundhaving at least two carboxylic acid groups with a compound having atleast two hydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an optionally substituted alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group described herein. The term “polyether” as used hereinis represented by the formula -(A¹O-A²O)_(a)—, where A¹ and A² can be,independently, an optionally substituted alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein and “a” is an integer of from 1 to 500. Examples of polyethergroups include polyethylene oxide, polypropylene oxide, and polybutyleneoxide.

The term “halide” as used herein refers to the halogens fluorine,chlorine, bromine, and iodine.

The term “hydroxyl” as used herein is represented by the formula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an optionally substituted alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein.

The term “azide” as used herein is represented by the formula —N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” as used herein is represented by the formula —CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an optionallysubstituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, —S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen oran optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.Throughout this specification “S(O)” is a short hand notation for S═O.The term “sulfonyl” is used herein to refer to the sulfo-oxo grouprepresented by the formula —S(O)₂A¹, where A¹ can be hydrogen or anoptionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “sulfone” as used herein is represented by the formulaA¹S(O)₂A², where A¹ and A² can be, independently, an optionallysubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein. The term“sulfoxide” as used herein is represented by the formula A¹S(O)A², whereA¹ and A² can be, independently, an optionally substituted alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

The term “organic residue” defines a carbon containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15,carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbonatoms, or 1 to 4 carbon atoms. In a further aspect, an organic residuecan comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbonatoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has the structure

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms,1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organicradical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbonatoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5,6,7,8-tetrahydro-2-naphthyl radical.In some embodiments, an organic radical can contain 1-10 inorganicheteroatoms bound thereto or therein, including halogens, oxygen,sulfur, nitrogen, phosphorus, and the like. Examples of organic radicalsinclude but are not limited to an alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, mono-substituted amino, di-substituted amino,acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide,alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy,substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl,heteroaryl, heterocyclic, or substituted heterocyclic radicals, whereinthe terms are defined elsewhere herein. A few non-limiting examples oforganic radicals that include heteroatoms include alkoxy radicals,trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals andthe like.

“Inorganic radicals,” as the term is defined and used herein, contain nocarbon atoms and therefore comprise only atoms other than carbon.Inorganic radicals comprise bonded combinations of atoms selected fromhydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, andhalogens such as fluorine, chlorine, bromine, and iodine, which can bepresent individually or bonded together in their chemically stablecombinations. Inorganic radicals have 10 or fewer, or preferably one tosix or one to four inorganic atoms as listed above bonded together.Examples of inorganic radicals include, but not limited to, amino,hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonlyknown inorganic radicals. The inorganic radicals do not have bondedtherein the metallic elements of the periodic table (such as the alkalimetals, alkaline earth metals, transition metals, lanthanide metals, oractinide metals), although such metal ions can sometimes serve as apharmaceutically acceptable cation for anionic inorganic radicals suchas a sulfate, phosphate, or like anionic inorganic radical. Inorganicradicals do not comprise metalloids elements such as boron, aluminum,gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gaselements, unless otherwise specifically indicated elsewhere herein.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

The following abbreviations are used herein. DMF: dimethyl formamide.EtOAc: ethyl acetate. THF: tetrahydrofuran. DIPEA or DIEA:diisopropylethylamine. HOBt: 1-hydroxybenzotriazole. EDC:1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride. DMSO:dimethylsulfoxide. DMAP: 4-Dimethylaminopyridine. RT: Room temperature.H: Hours. Min: Minutes. DCM: Dichloromethane. MeCN: Acetonitrile. MeOH:methanol. iPrOH: 2-Propanol. n-BuOH: 1-Butanol.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds can not be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

B. DEVELOPMENT OF NOVEL ALLOSTERIC POTENTIATORS OF mGluR5

Phencyclidine (PCP) and other NMDA receptor antagonists induce apsychotic state in humans similar to schizophrenia. In schizophreniapatients, PCP and ketamine exacerbate/precipitate preexisting positiveand negative symptoms in stable patients. Treatment with NMDA receptorco-agonists can improve positive and negative symptoms. A schematic ofthe NMDA receptor is shown in FIG. 1. Activation of mGluR5 potentiatesNMDA receptor function. See FIG. 2. Orthosteric ligands lack subtypeselectivity and may cause unwanted side effects. Allosteric modulators(see FIG. 3) targeting transmembrane domain offer alternative: TMD issignificantly less conserved.

4-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) is a potentand selective mGluR5 potentiator having modest efficacy in rodentbehavioral models for antipsychoticic activity. See FIG. 4. However,this compound lacks satisfactory aqueous solubility and exhibits poororal bioavailability. Approximately 160,000 compounds were screened aspotential mGluR5 modulators. After verification, compounds wereclassified as agonists, potentiators, and antagonists. See FIG. 5.

As shown below, based upon identified structures, an amide library couldbe prepared.

Typically, small, non-polar, and morpholino side chains gave highestpotency. Also, typically, increasing ring size and steric bulk decreasedactivity. Polar side chains were tolerated but typically decreasedactivity. Additionally, the side chains could be further modified, asshown below.

Relevant data are tabulated below. In general, methyl substitutionprovided superior results.

EC₅₀ % Glu Compound R (nM) Max 7a CH₃ 3.5 82.5 7b CH₂CH₂CH₃ 1250 90.1 7cCH(CH₃)₂ 1770 89.1 7d thiophene 1000 95 7e

1190 87 7f

1600 92 7g

2450 91

EC₅₀ % Glu Compound R (nM) Max 9a H  212 67.3 9b Me  89 82 9c n-propyl 423 59.8 9d thiophene 1470 43.7

Replacement of hydroxypiperidine with azitidine was tolerated, withsmall R-groups typically preferred.

EC₅₀ % Glu Compound X (nM) Max 19a 2-fluoro 27.3 80 19b 3-fluoro  3.2577 19c 4-fluoro 14.7 63 19d 3,4-difluoro 68.7 52 19e 3,5-difluoro  59367 19f 4-fluoro-3-methyl  500 76 19g 2,4-difluoro 1970 58 19h 4-methylinactive — 19i 3-trifluoromethyl 2060 68 19j 4-pyridinyl 7880 24 19k2-pyridinyl 2210 49 19l imidazole inactive — 19m cyclohexyl 1790 77

Typically, incorporation of mono-fluoro substituents increased potencyand efficacy.

Lead compounds were then identified; all identified compounds providednear maximal response, with 3-fluoro substitution and morpholino amideproviding satisfactory results.

EC₅₀ % Glu Compound X NRR′ (nM) Max 20a 20b 20c 20d 2-fluoro 3-fluoro4-fluoro 3,4-difluoro

 34.9  19.4  39.4   137  86  92  91  91 20e 20f 20g 20h 2-fluoro3-fluoro 4-fluoro 3,4-difluoro

 20.6  11.9  24.7  76.3  88  86  95 104 20i 20j 20k 20l 2-fluoro3-fluoro 4-fluoro 3,4-difluoro

 12.0  5.3  23.6  33.5 105 112 107 114 20m 20n 20o 20p 2-fluoro 3-fluoro4-fluoro 3,4-difluoro

166.2  59.5 155.5 314.0  98 104 103  88

Linkers were investigated as shown in the following schematic:

The displacement of [3H]methoxyPEPy was then investigated. The compoundswere found to bind to MPEP site with varying affinities. See FIG. 7. Thecompounds were also tested for activity on other receptors (e.g.,mGluR1, mGluR4, mGluR7, M3). Initial testing demonstrates selectivityfor mGluR5. The compounds were also tested for stability in rat livermicrosomes. Typically, the compounds retain 90% of parent over timecourse of 45 min

Compounds were then evaluated for activity on amphetamine-inducedhyperlocomotion. See FIG. 8, FIG. 9, and FIG. 10.

C. COMPOUNDS

In one aspect, the invention relates to compounds useful as positiveallosteric modulators (potentiators) of the metabotropic glutamatereceptor subtype 5 (mGluR5). More specifically, the present inventionrelates to compounds that allosterically modulate mGluR5 receptoractivity, affecting the sensitivity of mGluR5 receptors to agonistswithout acting as orthosteric agonists themselves. The compounds of theinvention are useful in the treatment neurological and psychiatricdisorders associated with glutamate dysfunction and other diseases inwhich metabotropic glutamate receptors are involved, as furtherdescribed herein.

In a further aspect, the invention relates to a compound orpharmaceutically acceptable salt thereof selected fromN-cyclopentyl-4-(phenylethynyl)benzamide;(4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;morpholino(4-(phenylethynyl)phenyl)methanone;(4-((3-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;N-cyclohexyl-4-(phenylethynyl)benzamide;(4-((3-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;4-(phenylethynyl)-N-propylbenzamide;(4-((4-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;N-(3,3-dimethylbutyl)-4-(phenylethynyl)benzamide;(4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;N-isopentyl-4-(phenylethynyl)benzamide;(4-((2-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-(3-methoxypropyl)-4-(phenylethynyl)benzamide;(4-(hydroxymethyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-butyl-4-(phenylethynyl)benzamide;(R)-4-(phenylethynyl)-N-(2-phenylpropyl)benzamide;(4-((3,4-difluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-hydroxy-4-methylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(hydroxymethyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-(pentan-2-ylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-(cyclohexylmethyl)-4-(phenylethynyl)benzamide;(4-((3-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;N-(2-cyclohexenylethyl)-4-(phenylethynyl)benzamide;N-(4-methylcyclohexyl)-4-(phenylethynyl)benzamide;(4-(cyclohexylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;N-(3-hydroxypropyl)-4-(phenylethynyl)benzamide;(2,6-dimethylmorpholino)(4-(phenylethynyl)phenyl)methanone;(4-(phenylethynyl)phenyl)(4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-1-yl)methanone;(3-hydroxy-3-methylazetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(S)-(4-(1-cyclohexylethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(4-methylpiperazin-1-yl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(3-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-(2-chlorophenethyl)-4-(phenylethynyl)benzamide;N-(2-morpholinoethyl)-4-(phenylethynyl)benzamide;N-(2,3-dihydro-1H-inden-1-yl)-4-(phenylethynyl)benzamide;(4-((3,4-difluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;N-(2,3-dihydro-1H-inden-2-yl)-4-(phenylethynyl)benzamide;(4-((4-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;(4-methylpiperazin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-(4-chlorophenethyl)-4-(phenylethynyl)benzamide;(4-((2-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;N-(3-chlorophenethyl)-4-(phenylethynyl)benzamide;(4-(cyclobutylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-(4-bromophenethyl)-4-(phenylethynyl)benzamide;(3-hydroxyazetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(2-morpholinoethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;N-(3,3-dimethylbutyl)-4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)benzamide;(4-(4-chloro-2-(trifluoromethyl)phenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(3-hydroxy-3-propylazetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(octahydroisoquinolin-2(1H)-yl)(4-(phenylethynyl)phenyl)methanone;(4-((4-fluoro-3-methylphenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-((3,5-difluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(S)—N-((1-ethylpyrrolidin-2-yl)methyl)-4-(phenylethynyl)benzamide;(4-hydroxy-4-(thiophen-2-yl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(azetidin-1-yl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-N-(3-methoxypropyl)benzamide;4-phenyl-1-(4-(phenylethynyl)benzoyl)piperidine-4-carbonitrile;N-(3,3-dimethylbutyl)-4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzamide;(4-isopropylpiperazin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(2-methoxyethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-(3-morpholinopropyl)-4-(phenylethynyl)benzamide;(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;1-(4-phenyl-1-(4-(phenylethynyl)benzoyl)piperidin-4-yl)ethanone;1-(1-(4-(phenylethynyl)benzoyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one;(4-hydroxy-4-propylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(3-hydroxy-3-(thiophen-2-yl)azetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(3-fluorophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;4-(phenylethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide;(4-hydroxy-4-isopropylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(cyclohexylethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(E)-(4-hydroxypiperidin-1-yl)(4-styrylphenyl)methanone;4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-N-propylbenzamide;(4-((2,4-difluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-(phenylethynyl)phenyl)(4-phenylpiperazin-1-yl)methanone;(4-(2-methoxyphenyl)piperazin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-hydroxypiperidin-1-yl)(4-((3-(trifluoromethyl)phenyl)ethynyl)phenyl)methanone;4-(3-phenyl-1,2,4-oxadiazol-5-yl)-N-propylbenzamide;(4-hydroxypiperidin-1-yl)(4-(pyridin-2-ylethynyl)phenyl)methanone;(4-(4-bromophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(cyclopropylmethylamino)piperidin-1-yl)(4-(phenylethyny)phenyl)methanone;(4-(phenylethynyl)phenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone;N-(2-(dimethylamino)ethyl)-4-(phenylethynyl)benzamide;N-(4-fluorophenyl)-4-(2-methylpiperidine-1-carbonyl)benzamide;N-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-(phenylethynyl)benzamide;(4-hydroxy-4-phenylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(phenylethynyl)phenyl)(4-(pyridin-4-yl)piperazin-1-yl)methanone;5-chloro-1-(4-(phenylethynyl)benzoyl)-3-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one;(4-(phenylethynyl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;2-(4-(4-(phenylethynyl)benzoyl)piperazin-1-yl)benzonitrile;(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenyl)(4-(pyridin-4-yl)piperazin-1-yl)methanone;(4-(phenylethynyl)phenyl)(piperazin-1-yl)methanone;(4-(2-fluorophenyl)piperazin-1-yl)(4-(phenylethynyl)phenyl)methanone;and(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone.

In a further aspect, the compound is selected from(2,6-dimethylmorpholino)(4-(phenylethynyl)phenyl)methanone;(3-hydroxy-3-(thiophen-2-yl)azetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(3-hydroxy-3-methylazetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(3-hydroxy-3-propylazetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(3-hydroxyazetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(3-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((2,4-difluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-((3,5-difluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-((3-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;(4-((3-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;(4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-((3-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-((4-fluoro-3-methylphenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-(2-fluorophenyl)piperazin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(2-methoxyethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(2-methoxyphenyl)piperazin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(2-morpholinoethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(3-fluorophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(4-bromophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(4-chloro-2-(trifluoromethyl)phenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(4-methylpiperazin-1-yl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(azetidin-1-yl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(cyclobutylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(cyclohexylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(cyclopropylmethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(hydroxymethyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(hydroxymethyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(pentan-2-ylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(phenylethynyl)phenyl)(4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-1-yl)methanone;(4-(phenylethynyl)phenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone;(4-(phenylethynyl)phenyl)(4-(pyridin-4-yl)piperazin-1-yl)methanone;(4-(phenylethynyl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;(4-(phenylethynyl)phenyl)(4-phenylpiperazin-1-yl)methanone;(4-(phenylethynyl)phenyl)(piperazin-1-yl)methanone;(4-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-hydroxy-4-(thiophen-2-yl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-hydroxy-4-isopropylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-hydroxy-4-methylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-hydroxy-4-phenylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-hydroxy-4-propylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-hydroxypiperidin-1-yl)(4-((3-(trifluoromethyl)phenyl)ethynyl)phenyl)methanone;(4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-isopropylpiperazin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-methylpiperazin-1-yl)(4-(phenylethynyl)phenyl)methanone;(octahydroisoquinolin-2(1H)-yl)(4-(phenylethynyl)phenyl)methanone;(R)-4-(phenylethynyl)-N-(2-phenylpropyl)benzamide;(S)-(4-(1-cyclohexylethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(S)—N-((1-ethylpyrrolidin-2-yl)methyl)-4-(phenylethynyl)benzamide;1-(1-(4-(phenylethynyl)benzoyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one;1-(4-phenyl-1-(4-(phenylethynyl)benzoyl)piperidin-4-yl)ethanone;2-(4-(4-(phenylethynyl)benzoyl)piperazin-1-yl)benzonitrile;4-(phenylethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide;4-(phenylethynyl)-N-propylbenzamide;4-phenyl-1-(4-(phenylethynyl)benzoyl)piperidine-4-carbonitrile;5-chloro-1-(4-(phenylethynyl)benzoyl)-3-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one;morpholino(4-(phenylethynyl)phenyl)methanone;N-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-(phenylethynyl)benzamide;N-(2-(dimethylamino)ethyl)-4-(phenylethynyl)benzamide;N-(2,3-dihydro-1H-inden-1-yl)-4-(phenylethynyl)benzamide;N-(2,3-dihydro-1H-inden-2-yl)-4-(phenylethynyl)benzamide;N-(2-chlorophenethyl)-4-(phenylethynyl)benzamide;N-(2-cyclohexenylethyl)-4-(phenylethynyl)benzamide;N-(2-morpholinoethyl)-4-(phenylethynyl)benzamide;N-(3,3-dimethylbutyl)-4-(phenylethynyl)benzamide;N-(3-chlorophenethyl)-4-(phenylethynyl)benzamide;N-(3-hydroxypropyl)-4-(phenylethynyl)benzamide;N-(3-methoxypropyl)-4-(phenylethynyl)benzamide;N-(3-morpholinopropyl)-4-(phenylethynyl)benzamide;N-(4-bromophenethyl)-4-(phenylethynyl)benzamide;N-(4-chlorophenethyl)-4-(phenylethynyl)benzamide;N-(4-methylcyclohexyl)-4-(phenylethynyl)benzamide;N-(cyclohexylmethyl)-4-(phenylethynyl)benzamide;N-butyl-4-(phenylethynyl)benzamide;N-cyclohexyl-4-(phenylethynyl)benzamide;N-cyclopentyl-4-(phenylethynyl)benzamide; andN-isopentyl-4-(phenylethynyl)benzamide.

In a further aspect, the compound is selected fromN-cyclopentyl-4-(phenylethynyl)benzamide;N-cyclohexyl-4-(phenylethynyl)benzamide;4-(phenylethynyl)-N-propylbenzamide;N-(3,3-dimethylbutyl)-4-(phenylethynyl)benzamide;N-isopentyl-4-(phenylethynyl)benzamide;N-(3-methoxypropyl)-4-(phenylethynyl)benzamide;N-butyl-4-(phenylethynyl)benzamide;(R)-4-(phenylethynyl)-N-(2-phenylpropyl)benzamide;N-(cyclohexylmethyl)-4-(phenylethynyl)benzamide;N-(2-cyclohexenylethyl)-4-(phenylethynyl)benzamide;N-(4-methylcyclohexyl)-4-(phenylethynyl)benzamide;N-(3-hydroxypropyl)-4-(phenylethynyl)benzamide;N-(2-chlorophenethyl)-4-(phenylethynyl)benzamide;N-(2-morpholinoethyl)-4-(phenylethynyl)benzamide;N-(2,3-dihydro-1H-inden-1-yl)-4-(phenylethynyl)benzamide;N-(2,3-dihydro-1H-inden-2-yl)-4-(phenylethynyl)benzamide;N-(4-chlorophenethyl)-4-(phenylethynyl)benzamide;N-(3-chlorophenethyl)-4-(phenylethynyl)benzamide;N-(4-bromophenethyl)-4-(phenylethynyl)benzamide;(S)—N-((1-ethylpyrrolidin-2-yl)methyl)-4-(phenylethynyl)benzamide;N-(3-morpholinopropyl)-4-(phenylethynyl)benzamide;4-(phenylethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide;N-(2-(dimethylamino)ethyl)-4-(phenylethynyl)benzamide; andN-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-(phenylethynyl)benzamide.

In a further aspect, the compound is selected from(4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;morpholino(4-(phenylethynyl)phenyl)methanone;(4-((3-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-((3-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(hydroxymethyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-hydroxy-4-methylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(hydroxymethyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-(pentan-2-ylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((3-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-(cyclohexylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;(2,6-dimethylmorpholino)(4-(phenylethynyl)phenyl)methanone;(4-(phenylethynyl)phenyl)(4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-1-yl)methanone;(3-hydroxy-3-methylazetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(S)-(4-(1-cyclohexylethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(4-methylpiperazin-1-yl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(3-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;(4-methylpiperazin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;(4-(cyclobutylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(3-hydroxyazetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(2-morpholinoethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;(4-(4-chloro-2-(trifluoromethyl)phenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(3-hydroxy-3-propylazetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(octahydroisoquinolin-2(1H)-yl)(4-(phenylethynyl)phenyl)methanone;(4-((4-fluoro-3-methylphenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-((3,5-difluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-hydroxy-4-(thiophen-2-yl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(azetidin-1-yl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;4-phenyl-1-(4-(phenylethynyl)benzoyl)piperidine-4-carbonitrile;(4-isopropylpiperazin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(2-methoxyethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;1-(4-phenyl-1-(4-(phenylethynyl)benzoyl)piperidin-4-yl)ethanone;1-(1-(4-(phenylethynyl)benzoyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one;(4-hydroxy-4-propylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(3-hydroxy-3-(thiophen-2-yl)azetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(3-fluorophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-hydroxy-4-isopropylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((2,4-difluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-(phenylethynyl)phenyl)(4-phenylpiperazin-1-yl)methanone;(4-(2-methoxyphenyl)piperazin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-hydroxypiperidin-1-yl)(4-((3-(trifluoromethyl)phenyl)ethynyl)phenyl)methanone;(4-(4-bromophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(cyclopropylmethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(phenylethynyl)phenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone;(4-hydroxy-4-phenylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(phenylethynyl)phenyl)(4-(pyridin-4-yl)piperazin-1-yl)methanone;5-chloro-1-(4-(phenylethynyl)benzoyl)-3-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one;(4-(phenylethynyl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;2-(4-(4-(phenylethynyl)benzoyl)piperazin-1-yl)benzonitrile;(4-(phenylethynyl)phenyl)(piperazin-1-yl)methanone;(4-(2-fluorophenyl)piperazin-1-yl)(4-(phenylethynyl)phenyl)methanone;and(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone.

In a further aspect, the compound is selected from4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-N-(3-methoxypropyl)benzamide;N-(3,3-dimethylbutyl)-4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzamide;4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-N-propylbenzamide;4-(3-phenyl-1,2,4-oxadiazol-5-yl)-N-propylbenzamide;(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenyl)(4-(pyridin-4-yl)piperazin-1-yl)methanone;N-(3,3-dimethylbutyl)-4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)benzamide;(E)-(4-hydroxypiperidin-1-yl)(4-styrylphenyl)methanone;(4-hydroxypiperidin-1-yl)(4-(pyridin-2-ylethynyl)phenyl)methanone;(4-(cyclohexylethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone; andN-(4-fluorophenyl)-4-(2-methylpiperidine-1-carbonyl)benzamide.

In a further aspect, the compound is selected from4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-N-(3-methoxypropyl)benzamide;N-(3,3-dimethylbutyl)-4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzamide;4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-N-propylbenzamide;4-(3-phenyl-1,2,4-oxadiazol-5-yl)-N-propylbenzamide;(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenyl)(4-(pyridin-4-yl)piperazin-1-yl)methanone;andN-(3,3-dimethylbutyl)-4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)benzamide.

In a yet further aspect, the compound is(E)-(4-hydroxypiperidin-1-yl)(4-styrylphenyl)methanone. In a yet furtheraspect, the compound is(4-hydroxypiperidin-1-yl)(4-(pyridin-2-ylethynyl)phenyl)methanone. In ayet further aspect, the compound is(4-(cyclohexylethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone. In ayet further aspect, the compound isN-(4-fluorophenyl)-4-(2-methylpiperidine-1-carbonyl)benzamide.

In a further aspect, the compound is selected fromN-cyclopentyl-4-(phenylethynyl)benzamide;(4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;morpholino(4-(phenylethynyl)phenyl)methanone;(4-((3-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;N-cyclohexyl-4-(phenylethynyl)benzamide;(4-((3-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;4-(phenylethynyl)-N-propylbenzamide;(4-((4-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;N-(3,3-dimethylbutyl)-4-(phenylethynyl)benzamide;(4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;N-isopentyl-4-(phenylethynyl)benzamide;(4-((2-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-(3-methoxypropyl)-4-(phenylethynyl)benzamide;(4-(hydroxymethyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-butyl-4-(phenylethynyl)benzamide;(R)-4-(phenylethynyl)-N-(2-phenylpropyl)benzamide;(4-((3,4-difluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-hydroxy-4-methylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(hydroxymethyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-(pentan-2-ylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-(cyclohexylmethyl)-4-(phenylethynyl)benzamide;(4-((3-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;N-(2-cyclohexenylethyl)-4-(phenylethynyl)benzamide;N-(4-methylcyclohexyl)-4-(phenylethynyl)benzamide;(4-(cyclohexylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;N-(3-hydroxypropyl)-4-(phenylethynyl)benzamide;(2,6-dimethylmorpholino)(4-(phenylethynyl)phenyl)methanone;(4-(phenylethynyl)phenyl)(4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-1-yl)methanone;(3-hydroxy-3-methylazetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(S)-(4-(1-cyclohexylethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(4-methylpiperazin-1-yl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(3-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-(2-chlorophenethyl)-4-(phenylethynyl)benzamide;N-(2-morpholinoethyl)-4-(phenylethynyl)benzamide;N-(2,3-dihydro-1H-inden-1-yl)-4-(phenylethynyl)benzamide;(4-((3,4-difluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;N-(2,3-dihydro-1H-inden-2-yl)-4-(phenylethynyl)benzamide;(4-((4-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;(4-methylpiperazin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-(4-chlorophenethyl)-4-(phenylethynyl)benzamide;(4-((2-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;N-(3-chlorophenethyl)-4-(phenylethynyl)benzamide;(4-(cyclobutylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-(4-bromophenethyl)-4-(phenylethynyl)benzamide;(3-hydroxyazetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(2-morpholinoethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;N-(3,3-dimethylbutyl)-4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)benzamide;(4-(4-chloro-2-(trifluoromethyl)phenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(3-hydroxy-3-propylazetidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(octahydroisoquinolin-2(1H)-yl)(4-(phenylethynyl)phenyl)methanone; and(4-((4-fluoro-3-methylphenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone.

In a further aspect, the compound is selected fromN-cyclopentyl-4-(phenylethynyl)benzamide;(4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;morpholino(4-(phenylethynyl)phenyl)methanone;(4-((3-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;N-cyclohexyl-4-(phenylethynyl)benzamide;(4-((3-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;4-(phenylethynyl)-N-propylbenzamide;(4-((4-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;N-(3,3-dimethylbutyl)-4-(phenylethynyl)benzamide;(4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;N-isopentyl-4-(phenylethynyl)benzamide;(4-((2-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;(4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-(3-methoxypropyl)-4-(phenylethynyl)benzamide;(4-(hydroxymethyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-butyl-4-(phenylethynyl)benzamide;(R)-4-(phenylethynyl)-N-(2-phenylpropyl)benzamide;(4-((3,4-difluorophenyl)ethynyl)phenyl)(morpholino)methanone;(4-((2-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-hydroxy-4-methylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-(hydroxymethyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((4-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone;(4-(pentan-2-ylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;N-(cyclohexylmethyl)-4-(phenylethynyl)benzamide;(4-((3-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;N-(2-cyclohexenylethyl)-4-(phenylethynyl)benzamide;N-(4-methylcyclohexyl)-4-(phenylethynyl)benzamide;(4-(cyclohexylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone;(4-((3,4-difluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;N-(3-hydroxypropyl)-4-(phenylethynyl)benzamide; and(2,6-dimethylmorpholino)(4-(phenylethynyl)phenyl)methanone.

In a further aspect, the compound is selected fromN-cyclopentyl-4-(phenylethynyl)benzamide;(4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone;morpholino(4-(phenylethynyl)phenyl)methanone; and(4-((3-fluorophenyl)ethynyl)phenyl)(morpholino)methanone.

In a still further aspect, the compound can be a phenylethynylbenzamidederivative, a cycloalkylethynylbenzamide derivative, a styrylbenzamidederivative, a 4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzamide derivative, a4-(pyridinylethynyl)benzamide derivative, or a N¹-phenylterephthalamidederivative.

1. Phenylethynylbenzamide Derivatives

In a further aspect, the invention relates to compounds having astructure represented by a formula:

wherein R¹ and R² are independently optionally substituted organicradicals comprising from 1 to 12 carbon atoms; wherein each

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; whereinZ¹, Z², and Z³ are independently selected from N and C—R⁴, with theproviso that no more than two of Z¹, Z², and Z³ are nitrogen; andwherein R⁴ comprises up to five substituents independently selected fromhydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substitutedalkyl or alkenyl or alkynyl, optionally substituted heteroalkyl orheteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl orcycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; or a pharmaceutically acceptable salt orN-oxide thereof, wherein the compound exhibits potentiation of mGluR5response to glutamate as an increase in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith rat mGluR5 in the presence of the compound, compared to theresponse to glutamate in the absence of the compound.

In a further aspect, R¹ and R² are independently alkyl having from 1 to6 carbons. In a further aspect, N, R¹, and R² together comprise anoptionally substituted heterocyclic ring having from two to sevencarbons. In a further aspect, all of Z¹, Z², and Z³ are carbon. In afurther aspect, R⁴ comprises up to five substituents independentlyselected from hydrogen, halogen, and lower alkyl. In a further aspect,both of Y¹ and Y² are carbon.

In a yet further aspect, the compound has a structure represented by aformula:

In a further aspect, R¹ and R² are independently alkyl having from 1 to6 carbons or N, R¹, and R² together comprise an optionally substitutedheterocyclic ring having from two to seven carbons; R comprises foursubstituents independently selected from hydrogen, halogen, and loweralkyl; and R⁴ comprises five substituents independently selected fromhydrogen, halogen, and lower alkyl.

In a further aspect, the invention relates to phenylethynylbenzamidederivatives. In one aspect, the compound is a compound orpharmaceutically acceptable salt thereof comprising the structure:

wherein R¹ and R² are independently selected from optionally substitutedalkyl or alkenyl or alkynyl, optionally substituted heteroalkyl orheteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl orcycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,and optionally substituted heteroaryl, or wherein N, R¹, and R² togethercomprise an optionally substituted hetrocyclic ring having from two toseven carbons; wherein R³ comprises four substituents independentlyselected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol,optionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkoxyl, optionally substitutedthioalkyl, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, and optionally substituted amino, thioamido,amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, andalkylamine-carbonyl; wherein R⁴ comprises five substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, optionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkoxyl, optionally substitutedthioalkyl, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, and optionally substituted amino, thioamido,amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, andalkylamine-carbonyl; and wherein the compound exhibits potentiation ofglutamate as an increase in response to non-maximal concentrations ofglutamate in human embryonic kidney cells transfected with rat mGluR5 inthe presence of the compound, compared to the response to glutamate inthe absence of the compound.

In one aspect, the compound exhibits potentiation with an EC₅₀ of lessthan about 10×10⁻⁶. For example, the compound can exhibit potentiationwith an EC₅₀ of less than about 10×10⁻⁷. As a further example, thecompound can exhibit potentiation with an EC₅₀ of less than about1.0×10⁸.

In a further aspect, R¹ is selected from optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,and optionally substituted heteroaryl and has from two to seven carbons.

In a further aspect, R² is selected from optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,and optionally substituted heteroaryl and has from two to seven carbons.

In a further aspect, one or more substitutents of R³ are selected fromoptionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl and have from two to seven carbons.

In a further aspect, one or more substitutents of R₄ are selected fromoptionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl and have from two to seven carbons.

In one aspect, each of R¹, R², R³, and/or R₄ comprises an optionallysubstituted alkyl or an optionally substituted cycloalkyl. In oneaspect, the optionally substituted alkyl of R¹, R², R³, and/or R₄comprises a C1 to C6 substituent; that is, a substituent having from oneto six carbons. For example, in one aspect, the optionally substitutedalkyl can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, or hexyl. In a further aspect, all of R³ arehydrogen.

In a further aspect, at least one of R⁴ is halogen selected from F andCl. In a further aspect, R⁴ comprises four hydrogens and one or twosubstituents selected from hydrogen, F, and Cl.

In one aspect, the compound can have a structure represented by aformula:

In one aspect, at least one of R⁴ is optionally substituted alkylselected from methyl and trifluoromethyl. In a further aspect, thecompound can have a structure represented by a formula:

In a further aspect, R⁴ comprises five hydrogens and one optionallysubstituted alkyl. In a further aspect, all of R⁴ are hydrogen.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, R¹ and R² are independently selected from hydrogen,(1-ethylpyrrolidin-2-yl)methyl; 2-(1-methylpyrrolidin-2-yl)ethyl;2-(dimethylamino)ethyl; 2-(piperidin-1-yl)ethyl;2,3-dihydro-1H-inden-1-yl; 2-chlorophenethyl; 2-morpholinoethyl;2-phenylpropyl; 3,3-dimethylbutyl; 3-chlorophenethyl; 3-hydroxypropyl;3-methoxypropyl; 3-morpholinopropyl; 4-bromophenethyl;4-chlorophenethyl; butyl; cyclohexenylethyl;cyclohexylcyclohexylmethylcyclopentyl; isopentyl; methylcyclohexyl; andpropyl. In a yet further aspect, R¹ and R² are independently selectedfrom (1-ethylpyrrolidin-2-yl)methyl; 2-(1-methylpyrrolidin-2-yl)ethyl;2-(dimethylamino)ethyl; 2-(piperidin-1-yl)ethyl;2,3-dihydro-1H-inden-1-yl; 2-chlorophenethyl; 2-morpholinoethyl;2-phenylpropyl; 3,3-dimethylbutyl; 3-chlorophenethyl; 3-hydroxypropyl;3-methoxypropyl; 3-morpholinopropyl; 4-bromophenethyl;4-chlorophenethyl; butyl; cyclohexenylethyl;cyclohexylcyclohexylmethylcyclopentyl; isopentyl; methylcyclohexyl; andpropyl.

In a still further aspect, the compound has a structure represented by aformula:

In a still further aspect, N, R¹, and R² together comprise a cyclicoptionally substituted alkyl residue. In a further aspect, the cyclicoptionally substituted alkyl residue is selected from(E)-4-hydroxypiperidin-1-yl;(S)-(4-(1-cyclohexylethylamino)piperidin-1-yl;1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one;1-(piperidin-4-yl)ethanone; 2-(piperazin-1-yl)benzonitrile;2,6-dimethylmorpholino; 2-morpholinoethyl;3-hydroxy-3-(thiophen-2-yl)azetidin-1-yl;3-hydroxy-3-methylazetidin-1-yl; 3-hydroxy-3-propylazetidin-1-yl;3-hydroxyazetidin-1-yl; 3-hydroxypiperidin-1-yl;4-(2-fluorophenyl)piperazin-1-yl; 4-(2-methoxyethylamino)piperidin-1-yl;4-(2-methoxyphenyl)piperazin-1-yl;4-(2-morpholinoethylamino)piperidin-1-yl;4-(3-fluorophenyl)-4-hydroxypiperidin-1-yl;4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-1-yl;4-(4-bromophenyl)-4-hydroxypiperidin-1-yl;4-(4-chloro-2-(trifluoromethyl)phenyl)-4-hydroxypiperidin-1-yl;4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl;4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl;4-(4-methylpiperazin-1-yl)piperidin-1-yl;4-(azetidin-1-yl)piperidin-1-yl; 4-(cyclobutylamino)piperidin-1-yl;4-(cyclopropylmethylamino)piperidin-1-yl;4-(hydroxymethyl)piperidin-1-yl; 4-(pyridin-2-yl)piperazin-1-yl;4-(pyrrolidin-1-yl)piperidin-1-yl;4-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl;4-hydroxy-4-(thiophen-2-yl)piperidin-1-yl;4-hydroxy-4-isopropylpiperidin-1-yl; 4-hydroxy-4-methylpiperidin-1-yl;4-hydroxypiperidin-1-yl; 4-isopropylpiperazin-1-yl;4-methylpiperazin-1-yl; 4-phenyl-1-piperidine-4-carbonitrile;6-chloro-1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one; morpholino;octahydroisoquinolin-2(1H)-yl; and piperazin-1-yl.

In a further aspect, the compound has a structure represented by aformula:

It is understood that the compound can be provided by the disclosedmethods of making, can be employed in the disclosed compositions, andcan be used in the disclosed methods of using.

2. Cycloalkylethynylbenzamide Derivatives

In one aspect, the invention relates to cycloalkylethynylbenzamidederivatives. In one aspect, the compound is a compound orpharmaceutically acceptable salt thereof comprising the structure:

wherein R¹ and R² are independently selected from hydrogen, optionallysubstituted alkyl or alkenyl or alkynyl, optionally substitutedheteroalkyl or heteroalkenyl or heteroalkynyl, optionally substitutedcycloalkyl or cycloalkenyl or cycloalkynyl, optionally substitutedheterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or wherein N,R¹, and R² together comprise an optionally substituted hetrocyclic ringhaving from two to seven carbons;

wherein R³ comprises four substituents independently selected fromhydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substitutedalkyl or alkenyl or alkynyl, optionally substituted heteroalkyl orheteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl orcycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl;

wherein Z comprises from zero to two carbons;

wherein R⁴ comprises nine to thirteen substituents independentlyselected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol,optionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkoxyl, optionally substitutedthioalkyl, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, and optionally substituted amino, thioamido,amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, andalkylamine-carbonyl; and

wherein the compound exhibits potentiation of glutamate as an increasein response to non-maximal concentrations of glutamate in humanembryonic kidney cells transfected with rat mGluR5 in the presence ofthe compound, compared to the response to glutamate in the absence ofthe compound.

In one aspect, the compound exhibits potentiation with an EC₅₀ of lessthan about 1.0×10⁻⁶. For example, the compound can exhibit potentiationwith an EC₅₀ of less than about 10×10⁻⁷. As a further example, thecompound can exhibit potentiation with an EC₅₀ of less than about1.0×10⁸.

In a further aspect, R¹ is selected from optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,and optionally substituted heteroaryl and has from two to seven carbons.

In a further aspect, R² is selected from optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,and optionally substituted heteroaryl and has from two to seven carbons.

In a further aspect, one or more substitutents of R³ are selected fromoptionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl and have from two to seven carbons.

In a further aspect, one or more substitutents of R⁴ are selected fromoptionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl and have from two to seven carbons.

In one aspect, the optionally substituted alkyl of R¹, R², R³, and/or R₄comprises an optionally substituted alkyl or an optionally substitutedcycloalkyl. In a further aspect, all of R³ are hydrogen. In a furtheraspect, N, R¹, and R² together comprise an optionally substitutedhetrocyclic ring having from two to seven carbons. In a further aspect,N, R¹, and R² together comprise 4-hydroxypiperidin-1-yl. In a furtheraspect, Z is one and R⁴ comprises eleven substituents. In a furtheraspect, at least one of R⁴ is halogen selected from F and Cl. In afurther aspect, all of R⁴ are hydrogen.

In one aspect, the compound has a structure represented by a formula:

It is understood that the compound can be provided by the disclosedmethods of making, can be employed in the disclosed compositions, andcan be used in the disclosed methods of using.

3. Styrylbenzamide Derivatives

In one aspect, the invention relates to a compound having a structurerepresented by a formula:

wherein R¹ and R² are independently hydrogen or an optionallysubstituted organic radical comprising from 1 to 12 carbon atoms;wherein each

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; whereinZ¹, Z², and Z³ are independently selected from N and C—R⁴, with theproviso that no more than two of Z¹, Z², and Z³ are nitrogen; wherein R⁴comprises up to five substituents independently selected from hydrogen,halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; and wherein R^(7a) and R^(7b) together form anoptionally substituted carbocyclic or heterocyclic ring having from twoto five carbons or are independently selected from hydrogen, halogen,hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising1 to 5 carbon atoms selected from optionally substituted C1-C6 alkyl orC2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkylor C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substitutedC3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionallysubstituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8heterocycloalkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkoxyl, optionally substitutedthioalkyl, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, and optionally substituted amino, thioamido,amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, andalkylamine-carbonyl; or a pharmaceutically acceptable salt or N-oxidethereof, wherein the compound exhibits potentiation of mGluR5 responseto glutamate as an increase in response to non-maximal concentrations ofglutamate in human embryonic kidney cells transfected with rat mGluR5 inthe presence of the compound, compared to the response to glutamate inthe absence of the compound.

In a further aspect, R¹ and R² are independently hydrogen or alkylhaving from 1 to 6 carbons. In a further aspect, N, R¹, and R² togethercomprise an optionally substituted heterocyclic ring having from two toseven carbons. In a further aspect, all of Z¹, Z², and Z³ are carbon. Ina further aspect, R⁴ comprises up to five substituents independentlyselected from hydrogen, halogen, and lower alkyl. In a further aspect,both of Y¹ and Y² are carbon. In a further aspect, both of R^(7a) andR^(7b) are hydrogen.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, R¹ and R² are independently hydrogen or alkylhaving from 1 to 6 carbons or N, R¹, and R² together comprise anoptionally substituted heterocyclic ring having from two to sevencarbons; R comprises four substituents independently selected fromhydrogen, halogen, and lower alkyl; and R⁴ comprises five substituentsindependently selected from hydrogen, halogen, and lower alkyl.

In one aspect, the invention relates to styrylbenzamide derivatives. Inone aspect, the compound is a compound or pharmaceutically acceptablesalt thereof comprising the structure:

wherein R¹ and R² are independently selected from hydrogen, optionallysubstituted alkyl or alkenyl or alkynyl, optionally substitutedheteroalkyl or heteroalkenyl or heteroalkynyl, optionally substitutedcycloalkyl or cycloalkenyl or cycloalkynyl, optionally substitutedheterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or wherein N,R¹, and R² together comprise an optionally substituted hetrocyclic ringhaving from two to seven carbons; wherein R³ comprises four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, optionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkoxyl, optionally substitutedthioalkyl, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, and optionally substituted amino, thioamido,amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, andalkylamine-carbonyl; wherein R⁴ comprises five substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, optionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkoxyl, optionally substitutedthioalkyl, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, and optionally substituted amino, thioamido,amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, andalkylamine-carbonyl; and wherein the compound exhibits potentiation ofglutamate as an increase in response to non-maximal concentrations ofglutamate in human embryonic kidney cells transfected with rat mGluR5 inthe presence of the compound, compared to the response to glutamate inthe absence of the compound.

In one aspect, the compound exhibits potentiation with an EC₅₀ of lessthan about 1.0×10⁻⁶. For example, the compound can exhibit potentiationwith an EC₅₀ of less than about 1.0×10⁻⁷. As a further example, thecompound can exhibit potentiation with an EC₅₀ of less than about1.0×10⁸.

In a further aspect, R¹ is selected from optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,and optionally substituted heteroaryl and has from two to seven carbons.

In a further aspect, R² is selected from optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,and optionally substituted heteroaryl and has from two to seven carbons.

In a further aspect, one or more substitutents of R³ are selected fromoptionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl and have from two to seven carbons.

In a further aspect, one or more substitutents of R⁴ are selected fromoptionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl and have from two to seven carbons.

In a further aspect, N, R¹, and R² together comprise an optionallysubstituted hetrocyclic ring having from two to seven carbons. In afurther aspect, N, R¹, and R² together comprise 4-hydroxypiperidin-1-yl.

In a further aspect, the optionally substituted alkyl of R¹, R², R³,and/or R₄ comprises an optionally substituted alkyl or an optionallysubstituted cycloalkyl. n a further aspect, all of R³ are hydrogen.

In a further aspect, at least one of R⁴ is halogen selected from F andCl. In a further aspect, all of R⁴ are hydrogen. In a further aspect,the compound has a structure represented by a formula:

It is understood that the compound can be provided by the disclosedmethods of making, can be employed in the disclosed compositions, andcan be used in the disclosed methods of using.

4. 4-(3-Phenyl-1,2,4-oxadiazol-5-yl)benzamide derivatives

In one aspect, the invention relates to a compound having a structurerepresented by a formula:

wherein R¹ and R² are independently optionally substituted organicradicals comprising from 1 to 12 carbon atoms; wherein each

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; whereinZ¹, Z², and Z³ are independently selected from N and C—R⁴, with theproviso that no more than two of Z¹, Z², and Z³ are nitrogen; andwherein R⁴ comprises up to five substituents independently selected fromhydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substitutedalkyl or alkenyl or alkynyl, optionally substituted heteroalkyl orheteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl orcycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; or a pharmaceutically acceptable salt orN-oxide thereof, wherein the compound exhibits potentiation of mGluR5response to glutamate as an increase in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith rat mGluR5 in the presence of the compound, compared to theresponse to glutamate in the absence of the compound.

In a further aspect, R¹ and R² are independently hydrogen or alkylhaving from 1 to 6 carbons. In a further aspect, N, R¹, and R² togethercomprise an optionally substituted heterocyclic ring having from two toseven carbons. In a further aspect, all of Z¹, Z², and Z³ are carbon. Ina further aspect, R⁴ comprises up to five substituents independentlyselected from hydrogen, halogen, and lower alkyl. In a further aspect,both of Y¹ and Y² are carbon.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, R¹ and R² are independently alkyl having from 1 to6 carbons or N, R¹, and R² together comprise an optionally substitutedheterocyclic ring having from two to seven carbons; R comprises foursubstituents independently selected from hydrogen, halogen, and loweralkyl; and R⁴ comprises five substituents independently selected fromhydrogen, halogen, and lower alkyl.

In one aspect, the invention relates to4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzamide derivatives. In one aspect,the compound is a compound or pharmaceutically acceptable salt thereofcomprising the structure:

wherein R¹ and R² are independently selected from optionally substitutedalkyl or alkenyl or alkynyl, optionally substituted heteroalkyl orheteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl orcycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,and optionally substituted heteroaryl, or wherein N, R¹, and R² togethercomprise an optionally substituted hetrocyclic ring having from two toseven carbons; wherein R³ comprises four substituents independentlyselected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol,optionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkoxyl, optionally substitutedthioalkyl, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, and optionally substituted amino, thioamido,amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, andalkylamine-carbonyl; wherein R⁴ comprises five substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, optionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkoxyl, optionally substitutedthioalkyl, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, and optionally substituted amino, thioamido,amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, andalkylamine-carbonyl; and wherein the compound exhibits potentiation ofglutamate as an increase in response to non-maximal concentrations ofglutamate in human embryonic kidney cells transfected with rat mGluR5 inthe presence of the compound, compared to the response to glutamate inthe absence of the compound.

In one aspect, the compound exhibits potentiation with an EC₅₀ of lessthan about 1.0×10⁻⁶. For example, the compound can exhibit potentiationwith an EC₅₀ of less than about 1.0×10⁻⁷. As a further example, thecompound can exhibit potentiation with an EC₅₀ of less than about1.0×10⁻⁸.

In a further aspect, R¹ is selected from optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,and optionally substituted heteroaryl and has from two to seven carbons.

In a further aspect, R² is selected from optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,and optionally substituted heteroaryl and has from two to seven carbons.

In a further aspect, one or more substitutents of R³ are selected fromoptionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl and have from two to seven carbons.

In a further aspect, one or more substitutents of R⁴ are selected fromoptionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl and have from two to seven carbons.

In a further aspect, N, R¹, and R² together comprise an optionallysubstituted hetrocyclic ring having from two to seven carbons. In afurther aspect, N, R¹, and R² together comprise4-(pyridin-4-yl)piperazin-1-yl.

In a further aspect, the optionally substituted alkyl of R¹, R², R³,and/or R₄ comprises an optionally substituted alkyl or an optionallysubstituted cycloalkyl. In a further aspect, R¹ and R² are independentlyselected from H; 3-methoxypropyl; 3,3-dimethylbutyl; and N-propyl.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, all of R³ are hydrogen. In a further aspect, atleast one of R⁴ is halogen selected from F and Cl. In a further aspect,four of R⁴ are hydrogen and one of R⁴ is F.

It is understood that the compound can be provided by the disclosedmethods of making, can be employed in the disclosed compositions, andcan be used in the disclosed methods of using.

5. 4-(Pyridinylethynyl)benzamide derivatives

In a further aspect, the invention relates to compounds having astructure represented by a formula:

wherein R¹ and R² are independently hydrogen or optionally substitutedorganic radicals comprising from 1 to 12 carbon atoms; wherein each

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; whereinZ¹, Z², and Z³ are independently selected from N and C—R⁴, with theproviso that only of Z¹, Z², and Z³ are nitrogen; and wherein R⁴comprises up to five substituents independently selected from hydrogen,halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; or a pharmaceutically acceptable salt orN-oxide thereof, wherein the compound exhibits potentiation of mGluR5response to glutamate as an increase in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith rat mGluR5 in the presence of the compound, compared to theresponse to glutamate in the absence of the compound.

In a further aspect, R¹ and R² are independently hydrogen or alkylhaving from 1 to 6 carbons. In a further aspect, N, R¹, and R² togethercomprise an optionally substituted heterocyclic ring having from two toseven carbons. In a further aspect, R⁴ comprises four substituentsindependently selected from hydrogen, halogen, and lower alkyl. In afurther aspect, both of Y¹ and Y² are carbon.

In a yet further aspect, the compound has a structure represented by aformula:

In a further aspect, R¹ and R² are independently alkyl having from 1 to6 carbons or N, R¹, and R² together comprise an optionally substitutedheterocyclic ring having from two to seven carbons; R comprises foursubstituents independently selected from hydrogen, halogen, and loweralkyl; and R⁴ comprises five substituents independently selected fromhydrogen, halogen, and lower alkyl.

In a yet further aspect, the invention relates to4-(pyridinylethynyl)benzamide derivatives. In one aspect, the compoundis a compound or pharmaceutically acceptable salt thereof comprising astructure selected from:

wherein R¹ and R² are independently selected from hydrogen, optionallysubstituted alkyl or alkenyl or alkynyl, optionally substitutedheteroalkyl or heteroalkenyl or heteroalkynyl, optionally substitutedcycloalkyl or cycloalkenyl or cycloalkynyl, optionally substitutedheterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or wherein N,R¹, and R² together comprise an optionally substituted hetrocyclic ringhaving from two to seven carbons; wherein R³ comprises four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, optionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkoxyl, optionally substitutedthioalkyl, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, and optionally substituted amino, thioamido,amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, andalkylamine-carbonyl; wherein R⁴ comprises four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, optionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkoxyl, optionally substitutedthioalkyl, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, and optionally substituted amino, thioamido,amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, andalkylamine-carbonyl; and wherein the compound exhibits potentiation ofglutamate as an increase in response to non-maximal concentrations ofglutamate in human embryonic kidney cells transfected with rat mGluR5 inthe presence of the compound, compared to the response to glutamate inthe absence of the compound.

In one aspect, the compound exhibits potentiation with an EC₅₀ of lessthan about 1.0×10⁻⁶. For example, the compound can exhibit potentiationwith an EC₅₀ of less than about 1.0×10⁻⁷. As a further example, thecompound can exhibit potentiation with an EC₅₀ of less than about1.0×10⁸.

In a further aspect, R¹ is selected from hydrogen, optionallysubstituted alkyl or alkenyl or alkynyl, optionally substitutedheteroalkyl or heteroalkenyl or heteroalkynyl, optionally substitutedcycloalkyl or cycloalkenyl or cycloalkynyl, optionally substitutedheterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionallysubstituted aryl, and optionally substituted heteroaryl and has from twoto seven carbons.

In a further aspect, R² is selected from hydrogen, optionallysubstituted alkyl or alkenyl or alkynyl, optionally substitutedheteroalkyl or heteroalkenyl or heteroalkynyl, optionally substitutedcycloalkyl or cycloalkenyl or cycloalkynyl, optionally substitutedheterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionallysubstituted aryl, and optionally substituted heteroaryl and has from twoto seven carbons.

In a further aspect, one or more substitutents of R³ are selected fromoptionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl and have from two to seven carbons.

In a further aspect, one or more substitutents of R₄ are selected fromoptionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl and have from two to seven carbons.

In a further aspect, the optionally substituted alkyl of R¹, R², R³,and/or R₄ comprises an optionally substituted alkyl or an optionallysubstituted cycloalkyl.

In a further aspect, N, R¹, and R² together comprise an optionallysubstituted hetrocyclic ring having from two to seven carbons. In afurther aspect, N, R¹, and R² together comprise 2-methylpiperidinyl.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, N, R¹, and R² together comprise a cyclic optionallysubstituted alkyl residue. In a further aspect, the cyclic optionallysubstituted alkyl residue is 2-methylpiperidinyl. In a further aspect,all of R³ are hydrogen. In a further aspect, at least one of R⁴ ishalogen selected from F and Cl. In a further aspect, all of R⁴ arehydrogen. In a further aspect, the compound has a structure representedby a formula:

It is understood that the compound can be provided by the disclosedmethods of making, can be employed in the disclosed compositions, andcan be used in the disclosed methods of using.

6. N¹-Phenylterephthalamide Derivatives

In one aspect, the invention relates to a compound having a structurerepresented by a formula:

wherein R¹ and R² are independently hydrogen or an optionallysubstituted organic radical comprising from 1 to 12 carbon atoms;wherein each

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; whereinZ¹, Z², and Z³ are independently selected from N and C—R⁴, with theproviso that no more than two of Z¹, Z², and Z³ are nitrogen; wherein R⁴comprises up to five substituents independently selected from hydrogen,halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; and wherein R⁸ is selected from hydrogen andlower alkyl; or a pharmaceutically acceptable salt or N-oxide thereof,wherein the compound exhibits potentiation of mGluR5 response toglutamate as an increase in response to non-maximal concentrations ofglutamate in human embryonic kidney cells transfected with rat mGluR5 inthe presence of the compound, compared to the response to glutamate inthe absence of the compound.

In a further aspect, R¹ and R² are independently hydrogen or alkylhaving from 1 to 6 carbons. In a further aspect, N, R¹, and R² togethercomprise an optionally substituted heterocyclic ring having from two toseven carbons. In a further aspect, all of Z¹, Z², and Z³ are carbon. Ina further aspect, R⁴ comprises up to five substituents independentlyselected from hydrogen, halogen, and lower alkyl. In a further aspect,both of Y¹ and Y² are carbon. In a further aspect, R⁸ is hydrogen.

In a yet further aspect, the compound has a structure represented by aformula:

In a further aspect, R¹ and R² are independently hydrogen or alkylhaving from 1 to 6 carbons or N, R¹, and R² together comprise anoptionally substituted heterocyclic ring having from two to sevencarbons; R comprises four substituents independently selected fromhydrogen, halogen, and lower alkyl; and R⁴ comprises five substituentsindependently selected from hydrogen, halogen, and lower alkyl.

In one aspect, the invention relates to N¹-phenylterephthalamidederivatives. In one aspect, the compound is a compound orpharmaceutically acceptable salt thereof comprising the structure:

wherein R¹ and R² are independently selected from hydrogen, optionallysubstituted alkyl or alkenyl or alkynyl, optionally substitutedheteroalkyl or heteroalkenyl or heteroalkynyl, optionally substitutedcycloalkyl or cycloalkenyl or cycloalkynyl, optionally substitutedheterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or wherein N,R¹, and R² together comprise an optionally substituted hetrocyclic ringhaving from two to seven carbons; wherein R³ comprises four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, optionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkoxyl, optionally substitutedthioalkyl, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, and optionally substituted amino, thioamido,amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, andalkylamine-carbonyl; wherein R⁴ comprises five substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, optionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkoxyl, optionally substitutedthioalkyl, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, and optionally substituted amino, thioamido,amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, andalkylamine-carbonyl; and wherein the compound exhibits potentiation ofglutamate as an increase in response to non-maximal concentrations ofglutamate in human embryonic kidney cells transfected with rat mGluR5 inthe presence of the compound, compared to the response to glutamate inthe absence of the compound.

In one aspect, the compound exhibits potentiation with an EC₅₀ of lessthan about 1.0×10⁻⁶. For example, the compound can exhibit potentiationwith an EC₅₀ of less than about 1.0×10⁻⁷. As a further example, thecompound can exhibit potentiation with an EC₅₀ of less than about1.0×10⁸.

In a further aspect, R¹ is selected from optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,and optionally substituted heteroaryl and has from two to seven carbons.

In a further aspect, R² is selected from optionally substituted alkyl oralkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenylor heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl orcycloalkynyl, optionally substituted heterocycloalkyl orheterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl,and optionally substituted heteroaryl and has from two to seven carbons.

In a further aspect, one or more substitutents of R³ are selected fromoptionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl and have from two to seven carbons.

In a further aspect, one or more substitutents of R⁴ are selected fromoptionally substituted alkyl or alkenyl or alkynyl, optionallysubstituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionallysubstituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionallysubstituted heterocycloalkyl or heterocycloalkenyl orheterocycloalkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl and have from two to seven carbons.

In a further aspect, N, R¹, and R² together comprise an optionallysubstituted hetrocyclic ring having from two to seven carbons. In afurther aspect, N, R¹, and R² together comprise 2-methylpiperidinyl.

In a further aspect, the optionally substituted alkyl of R¹, R², R³,and/or R₄ comprises an optionally substituted alkyl or an optionallysubstituted cycloalkyl. In a further aspect, all of R³ are hydrogen.

In a further aspect, at least one of R⁴ is halogen selected from F andCl. In a further aspect, four of R⁴ are hydrogen and one of R⁴ is F. Ina further aspect, the compound has a structure represented by a formula:

It is understood that the compound can be provided by the disclosedmethods of making, can be employed in the disclosed compositions, andcan be used in the disclosed methods of using.

D. METABOTROPIC GLUTAMATE RECEPTOR ACTIVITY

The utility of the compounds in accordance with the present invention aspotentiators of metabotropic glutamate receptor activity, in particularmGluR5 activity, can be demonstrated by methodology known in the art.Human embryonic kidney (HEK) cells transfected with rat mGluR5 wereplated in clear bottom assay plates for assay in a Functional DrugScreening System (FDSS). The cells were loaded with a Ca²⁺-sensitivefluorescent dye (e.g., Fluo-4), and the plates were washed and placed inthe FDSS instrument. After establishment of a fluorescence baseline fortwelve seconds, the compounds of the present invention were added to thecells, and the response in cells was measured. Five minutes later, anmGluR5 agonist (e.g., glutamate, 3,5-dihydroxyphenylglycine, orquisqualate) was added to the cells, and the response of the cells wasmeasured. Potentiation of the agonist response of mGluR5 by thecompounds in the present invention was observed as an increase inresponse to non-maximal concentrations of agonist (here, glutamate) inthe presence of compound compared to the response to agonist in theabsence of compound.

The above described assay operated in two modes. In the first mode, arange of concentrations of the present compounds were added to cells,followed by a single fixed concentration of agonist. If a compound actedas a potentiator, an EC₅₀ value for potentiation and a maximum extent ofpotentiation by the compound at this concentration of agonist wasdetermined by non-linear curve fitting. In the second mode, severalfixed concentrations of the present compounds were added to variouswells on a plate, followed by a range of concentrations of agonist foreach concentration of present compound; the EC₅₀ values for the agonistat each concentration of compound were determined by non-linear curvefitting. A decrease in the EC₅₀ value of the agonist with increasingconcentrations of the present compounds (a leftward shift of the agonistconcentration-response curve) is an indication of the degree of mGluR5potentiation at a given concentration of the present compound. Anincrease in the EC₅₀ value of the agonist with increasing concentrationsof the present compounds (a rightward shift of the agonistconcentration-response curve) is an indication of the degree of mGluR5antagonism at a given concentration of the present compound. The secondmode also indicates whether the present compounds also affect themaximum response to mGluR5 to agonists.

In particular, the disclosed compounds had activity in potentiating themGluR5 receptor in the aforementioned assays, generally with an EC₅₀ forpotentiation of less than about 10 μM. Preferred compounds within thepresent invention had activity in potentiating the mGluR5 receptor withan EC₅₀ for potentiation of less than about 500 nM. Preferred compoundsfurther caused a leftward shift of the agonist EC₅₀ by greater than3-fold. These compounds did not cause mGluR5 to respond in the absenceof agonist, and they did not elicit a significant increase in themaximal response of mGluR5 to agonists. These compounds are positiveallosteric modulators (potentiators) of human and rat mGluR5 and wereselective for mGluR5 compared to the other seven subtypes ofmetabotropic glutamate receptors.

With respect to the disclosed compounds, EC₅₀ for potentiating themGluR5 receptor are listed in Table 1 below:

TABLE 1 mGluR5 Potentiator EC₅₀ Nomenclature

2.78E-09 N-cyclopentyl-4-(phenylethynyl)benzamide

3.25E-09 (4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone

5.28E-09 morpholino(4- (phenylethynyl)phenyl)methanone

5.32E-09 (4-((3- fluorophenyl)ethynyl)phenyl)(morpholino) methanone

6.22E-09 N-cyclohexyl-4-(phenylethyl)benzamide

1.19E-08 (4-((3-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone

1.20E-08 (4-((2- fluorophenyl)ethynyl)phenyl)(morpholino) methanone

1.43E-08 (4-hydroxypiperidin-1-yl)(4- (phenylethynyl)phenyl)methanone

1.47E-08 4-(phenylethynyl)-N-propylbenzamide

1.52E-08 (4-((4-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone

1.94E-08 N-(3,3-dimethylbutyl)-4- (phenylethynyl)benzamide

2.06E-08 (4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone

2.36E-08 (4-((2-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone

2.47E-08 (4-((4- fluorophenyl)ethynyl)phenyl)(morpholino) methanone

2.61E-08 (4-((4- fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone

2.73E-08 N-isopentyl-4-(phenylethynyl)benzamide

2.81E-08 (4-((2- fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone

2.83E-08 (4-hydroxypiperidin-1-yl)(4- (phenylethynyl)phenyl)methanone

3.22E-08 N-(3-methoxypropyl)-4- (phenylethynyl)benzamide

3.27E-08 (4-(hydroxymethyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

3.35E-08 N-butyl-4-(phenylethynyl)benzamide

3.49E-08 (R)-4-(phenylethynyl)-N-(2- phenylpropyl)benzamide

3.51E-08 (4-((3,4-difluoro- phenyl)ethynyl)phenyl)(morpholino)methanone

3.79E-08 (4-((2- fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone

3.94E-08 (4-hydroxy-4-methylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

4.34E-08 (4-(hydroxymethyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

5.42E-08 (4-((4-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone

5.95E-08 (4-(pentan-2-ylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

6.87E-08 N-(cyclohexylmethyl)-4- (phenylethynyl)benzamide

7.30E-08 (4-((3-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone

7.39E-08 (4-((3,4-difluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone

7.53E-08 N-(2-cyclohexenylethyl)-4- (phenylethynyl)benzamide

7.63E-08 N-(4-methylcyclohexyl)-4- (phenylethynyl)benzamide

7.80E-08 (4-(cyclohexylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

8.17E-08 (4-((3,4-difluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin-1-yl)methanone

8.62E-08 N-(3-hydroxypropyl)-4- (phenylethynyl)benzamide

8.89E-08 (2,6-dimethylmorpholino)(4- (phenylethynyl)phenyl)methanone

1.13E-07 (4-(phenylethynyl)phenyl)(4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-1-yl)methanone

1.19E-07 (3-hydroxy-3-methylazetidin-1-yl)(4-(phenylethynyl)phenyl)methanone

1.29E-07 (S)-(4-(1-cyclohexylethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

1.32E-07 (4-(4-methylpiperazin-1-yl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

1.34E-07 (3-hydroxypiperidin-1-yl)(4- (phenylethynyl)phenyl)methanone

1.35E-07 N-(2-chlorophenethyl)-4- (phenylethynyl)benzamide

1.37E-07 N-(2-morpholinoethyl)-4- (phenylethynyl)benzamide

1.46E-07 N-(2,3-dihydro-1H-inden-1-yl)-4- (phenylethynyl)benzamide

1.56E-07 (4-((3,4-difluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone

1.59E-07 N-(2,3-dihydro-1H-inden-2-yl)-4- (phenylethynyl)benzamide

1.62E-07 (4-((4-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone

1.66E-07 (4-methylpiperazin-1-yl)(4- (phenylethynyl)phenyl)methanone

1.77E-07 N-(4-chlorophenethyl)-4- (phenylethynyl)benzamide

1.87E-07 (4-((2-fluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone

2.06E-07 N-(3-chlorophenethyl)-4- (phenylethynyl)benzamide

2.12E-07 (4-(cyclobutylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

2.37E-07 N-(4-bromophenethyl)-4- (phenylethynyl)benzamide

3.14E-07 (3-hydroxyazetidin-1-yl)(4- (phenylethynyl)phenyl)methanone

3.83E-07 (4-(2-morpholinoethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

3.87E-07 (4-((3,4-difluorophenyl)ethynyl)phenyl)(3-hydroxyazetidin-1-yl)methanone

4.23E-07 N-(3,3-dimethylbutyl)-4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)benzamide

4.77E-07 (4-(4-chloro-2-(trifluoromethyl)phenyl)-4-hydroxypiperidin-1-yl)(4- (phenylethynyl)phenyl)methanone

5.00E-07 (3-hydroxy-3-propylazetidin-1-yl)(4-(phenylethynyl)phenyl)methanone

5.93E-07 (octahydroisoquinolin-2(1H)-yl)(4-(phenylethynyl)phenyl)methanone

8.32E-07 (4-((4-fluoro-3- methylphenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone

1.00E-06 (4-((3,5-difluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone

1.03E-06 (S)-N-((1-ethylpyrrolidin-2-yl)methyl)-4-(phenylethynyl)benzamide

1.07E-06 (4-hydroxy-4-(thiophen-2-yl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

1.11E-06 (4-(azetidin-1-yl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

1.12E-06 4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-N-(3-methoxypropyl)benzamide

1.14E-06 4-phenyl-1-(4- (phenylethynyl)benzoyl)piperidine-4-carbonitrile

1.16E-06 N-(3,3-dimethylbutyl)-4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzamide

1.19E-06 (4-isopropylpiperazin-1-yl)(4- (phenylethynyl)phenyl)methanone

1.19E-06 (4-(2-methoxyethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

1.23E-06 N-(3-morpholinopropyl)-4- (phenylethynyl)benzamide

1.25E-06 (4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

1.25E-06 1-(4-phenyl-1-(4- (phenylethynyl)benzoyl)piperidin-4-yl)ethanone

1.47E-06 1-(1-(4-(phenylethynyl)benzoyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

1.61E-06 (4-hydroxy-4-propylpiperidn-1-yl)(4-(phenylethynyl)phenyl)methanone

1.71E-06 (3-hydroxy-3-(thiophen-2-yl)azetidin-1-yl)(4-(phenylethynyl)phenyl)methanone

1.77E-06 (4-(3-fluorophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

1.79E-06 4-(phenylethynyl)-N-(2-(piperidin-1- yl)ethyl)benzamide

1.80E-06 (4-hydroxy-4-isopropylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

1.87E-06 (4-(cyclohexylethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone

1.97E-06 (E)-(4-hydroxypiperidin-1-yl)(4- styrylphenyl)methanone

2.03E-06 4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5- yl)-N-propylbenzamide

2.03E-06 (4-((2,4-difluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin-1-yl)methanone

2.06E-06 (4-(phenylethynyl)phenyl)(4- phenylpiperazin-1-yl)methanone

2.10E-06 (4-(2-methoxyphenyl)piperazin-1-yl)(4-(phenylethynyl)phenyl)methanone

2.21E-06 (4-hydroxypiperidin-1-yl)(4-((3-(trifluoromethyl)phenyl)ethynyl)phenyl) methanone

2.27E-06 4-(3-phenyl-1,2,4-oxadiazol-5-yl)-N- propylbenzamide

2.45E-06 (4-hydroxypiperidin-1-yl)(4-pyridin-2-ylethynyl)phenyl)methanone

2.46E-06 (4-(4-bromophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

2.63E-06 (4-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

2.79E-06 (4-(cyclopropylmethylamino)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

2.92E-06 (4-(phenylethynyl)phenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone

2.99E-06 N-(2-(dimethylamino)ethyl)-4- (phenylethynyl)benzamide

3.33E-06 N-(4-fluorophenyl)-4-(2-methylpiperidine- 1-carbonyl)benzamide

3.53E-06 N-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-(phenylethynyl)benzamide

3.66E-06 (4-hydroxy-4-phenylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

3.68E-06 (4-(phenylethynyl)phenyl)(4-(pyridin-4-yl)piperazin-1-yl)methanone

3.72E-06 5-chloro-1-(4-(phenylethynyl)benzoyl)-3-(piperidin-4-yl)-1H-benzo[d]imidazol- 2(3H)-one

3.73E-06 (4-(phenylethynyl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone

4.20E-06 2-(4-(4-phenylethynyl)benzoyl)piperazin- 1-yl)benzonitrile

4.21E-06 (4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenyl)(4-(pyridin-4-yl)piperazin-1- yl)methanone

4.79E-06 (4-(phenylethynyl)phenyl)(piperazin-1- yl)methanone

5.14E-06 (4-(2-fluorophenyl)piperazin-1-yl)(4-(phenylethynyl)phenyl)methanone

6.46E-06 (4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

Preferred compounds of the present invention also showed in vivoefficacy in a number of preclinical rat behavioral model where known,clinically useful antipsychotics display similar positive responses. Forexample, compounds of the present invention reverse amphetamine-inducedhyperlocomotion in male Sprague-Dawley rats at doses ranging from 1 to100 mg/kg i.p. Data for three example compounds follow:

FIG. 8 shows efficacy in reversing amphetamine-induced hyperlocomotionfor (4-hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone(Compound VU13; In vitro: 13.6 nm; 50% Glu Max).

FIG. 9 shows efficacy in reversing amphetamine-induced hyperlocomotionfor (4-hydroxy-4-propylpiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone(Compound VU60/C109B2; In vitro: 1250 nm; 90% Glu Max).

FIG. 10 shows efficacy in reversing amphetamine-induced hyperlocomotionfor (4-(hydroxymethyl)piperidin-1-yl)(4-(phenylethynyl)phenyl)methanone(Compound VU14/C104B2; In vitro: 29.6 nm; 41% Glu Max).

Schizophrenic patients show decreased measures of sensorimotor gating,such as prepulse inhibition (PPI) of startle, and preclinical models ofPPI in rats are routinely used to predict antipsychotic efficacy. Infact, PPI can be measured in humans and rats employing identicalstimulus parameters yielding similar responses (Braff, D. L.; Geyer, M.A.; Swerdlow, N. R. ‘Human studies of prepulse inhibition of startle:normal subjects, patient groups, and pharmacological studies.’Psychopharmacology 2001, 156(2-3), 234-258; Braff, D. L.; Geyer, M. A.‘Sensorimotor gating and schizophrenia. Human and animal model studies.’Archives of general psychiatry 1990, 47(2), 181-8; Braff, D. L.; Geyer,M. A.; Swerdlow, N. R. ‘Human studies of prepulse inhibition of startle:normal subjects, patient groups, and pharmacological studies.’Psychopharmacology 2001, 156(2-3), 234-258; Weiss, I. C.; Feldon, J.‘Environmental animal models for sensor motor gating deficiencies inschizophrenia: a review.’ Psychopharmacology 2001, 156(2-3), 305-326;Thomsen, M.; Woertwein, G.; Fink-Jensen, A.; Woldbye, D. P. D.; Wess,J.; Caine, S. B. ‘Decreased prepulse inhibition and increasedsensitivity to muscarinic, but not dopaminergic drugs in M5 muscarinicacetylcholine receptor knockout mice.’ Psychopharmacology 2007, 192(1),97-110.). In addition, all clinically relevant antipsychotic agents(both typical and atypical) display efficacy in preclinical models ofPPI and amphetamine-induced hyperlocomotion, and these preclinicalmodels are employed to guide the development of novel antipsychoticagents (Geyer, M. A. ‘Behavioral studies of hallucinogenic drugs inanimals: implications for schizophrenia research.’ Pharmacopsychiatry1998, 31(Suppl. 2), 73-79; Geyer, M. A.; Mcllwain, K. L.; Paylor, R.‘Mouse genetic models for prepulse inhibition: an early review.’Molecular Psychiatry 2002, 7(10), 1039-1053; Powell, S. B.; Risbrough,V. B.; Geyer, M. A. ‘Potential use of animal models to examineantipsychotic prophylaxis for schizophrenia.’ Clinical NeuroscienceResearch 2003, 3(4-5), 289-296.).

Positive allosteric modulators (PAMs) of mGluR5 from distinct structuralseries (FIG. 12) have displayed antipsychotic-like effects in ratbehavioral models predictive of antipsychotic efficacy in humans(Lindsley, C. W.; Wisnoski, D. D.; Leister, W. H.; O'Brien, J. A.;Lemiare, W.; Williams, Jr., D. L.; Burno, M.; Sur, C.; Kinney, G. G.;Pettibone, D. J.; Miller, P. R.; Smith, S.; Duggan, M. E.; Hartman, G.D.; Conn, P. J.; Huff, J. R. ‘Discovery of positive allostericmodulators for the metabotropic glutamate receptor subtype 5 from aseries of N-(1,3-Diphenyl-1H-pyrazol-5-yl)benzamides that potentiatereceptor function in vivo’ J. Med. Chem. 2004, 47, 5825; Kinney, G. G.;O'Brien, Lemaire, W.; Burno, M.’ Bickel, D. J.; Clements, M. K.;Wisnoski, D. D.; Lindsley, C. W.; Tiller, P. R.; Smith, S.; Jacobson, M.A.; Sur, C.; Duggan, M. E.; Pettibone, D. J.; Williams, Jr., D. W. ‘Anovel selective allosteric modulator of metabotropic glutamate receptorsubtype 5 (mGluR5) has an antipsychotic profile in rat behavioralmodels’ J. Pharmacol. Exp. Therapeut. 2005, 313(1), 199; Epping-JordanM. P., Nayak, S., Derouet, F., Dominguez, H., Bessis A. S., Le Poul E.,Ludwig B. L. Mutel V., Poli S. M. and Rocher J. P. In VivoCharacterization of mGluR5 Positive Allosteric Modulators as NovelTreatments for Schizophrenia and Cognitive Dysfunction Neuropharmacology2005, 49, 243).

CDPPB (Lindsley, C. W.; Wisnoski, D. D.; Leister, W. H.; O'Brien, J. A.;Lemiare, W.; Williams, Jr., D. L.; Burno, M.; Sur, C.; Kinney, G. G.;Pettibone, D. J.; iller, P. R.; Smith, S.; Duggan, M. E.; Hartman, G.D.; Conn, P. J.; Huff, J. R. ‘Discovery of positive allostericmodulators for the metabotropic glutamate receptor subtype 5 from aseries of N-(1,3-Diphenyl-1H-pyrazol-5-yl)benzamides that potentiatereceptor function in vivo’ J. Med. Chem. 2004, 47, 5825; Kinney, G. G.;O'Brien, Lemaire, W.; Burno, M.’ Bickel, D. J.; Clements, M. K.;Wisnoski, D. D.; Lindsley, C. W.; Tiller, P. R.; Smith, S.; Jacobson, M.A.; Sur, C.; Duggan, M. E.; Pettibone, D. J.; Williams, Jr., D. W. ‘Anovel selective allosteric modulator of metabotropic glutamate receptorsubtype 5 (mGluR5) has an antipsychotic profile in rat behavioralmodels’ J. Pharmacol. Exp. Therapeut. 2005, 313(1), 199) was the firstcentrally active mGlur5 PAM which reversed amphetamine-inducedhyperlomotion in rats, and recent data with the structurally distinctADX47273 afforded similar results (FIG. 13). Recently, similar data hasbeen reported with DFB. A new mGluR5 PAM (FIG. 14; VU000013) affordssimilar results as well, suggesting positive allosteric modulation ofmGluR5 provides antipsychotic-like efficacy in this preclinical model.

Both CDPPB and ADX47273 also demonstrated efficacy in PPI, a preclinicalmodel with direct relevance to clinical efficacy, and a behavioridentical in schizophrenic patients. As shown in FIG. 15, CDPPB reversesPPI in a dose-dependent manner at four different prepulse intensitiesabove background. ADX47273 affords similar results (FIG. 16).

E. METHODS OF MAKING THE COMPOUNDS

In one aspect, the invention relates to methods of making compoundsuseful as positive allosteric modulators (potentiators) of themetabotropic glutamate receptor subtype 5 (mGluR5), which can be usefulin the treatment neurological and psychiatric disorders associated withglutamate dysfunction and other diseases in which metabotropic glutamatereceptors are involved. In a further aspect, the invention relates tomethods of making phenylethynylbenzamide derivatives,cycloalkylethynylbenzamide derivatives, styrylbenzamide derivatives,4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzamide derivatives,4-(pyridinylethynyl)benzamide derivatives, and N¹-phenylterephthalamidederivatives.

1. Phenylethynylbenzamide Derivatives

In one aspect, the invention relates to a method for preparing aphenylethynylbenzamide derivative comprising the steps of coupling anarylacetylene with an aryl halide, wherein one of the arylacetylene orthe aryl halide bears a carboxyl functionality; and forming an amidederivative of the carboxyl functionality by reaction with an amine.Typically, a method involves a coupling reaction (e.g., transition metalcatalyzed cross coupling reaction) and a reaction forming an amidemoiety. Such a method can be represented in the following schematic:

In a further aspect, the method can be represented in the followingschematic, which illustrates a synthetic method useful for preparationof larger amounts of the disclosed compounds:

In one aspect, the coupling step is performed prior to the forming step.In a further aspect, the method further comprises the step of convertingthe carboxyl functionality to a carboxylic acid. In one aspect, thecarboxyl functionality is an ester moiety. In one aspect, the arylhalide bears the carboxyl functionality. The halide can be Br or I. Itis understood that a pseudohalide can be substituted for a halide.

In one aspect, the amine is an optionally substituted primary amine oran optionally substituted secondary amine. In a further aspect, theamine is an optionally substituted cyclic amine.

In one aspect, the coupling step is palladium-catalyzed cross-coupling.

In one aspect, the forming step is performed with PS-carbodiimide and1-hydroxybenzotriazole.

In one aspect, the aryl halide has a structure represented by a formula:

wherein R is optionally substituted alkyl; and wherein R³ comprises foursubstituents independently selected from hydrogen, halogen, andoptionally substituted alkyl.

In a further aspect, the arylacetylene has a structure represented by aformula:

wherein R⁴ comprises five substituents independently selected fromhydrogen, halogen, and optionally substituted alkyl.

It is understood that the method can be used to provide the disclosedcompounds.

2. Cycloalkylethynylbenzamide Derivatives

In one aspect, the invention relates to a method for preparing acycloalkylethynylbenzamide derivative comprising the steps of couplingan cycloalkylacetylene with an aryl halide, wherein the aryl halidebears a carboxyl functionality; and forming an amide derivative of thecarboxyl functionality by reaction with an amine. Typically, a methodinvolves a coupling reaction (e.g., transition metal catalyzed crosscoupling reaction) and a reaction forming an amide moiety. Such a methodcan be represented in the following schematic:

In one aspect, the coupling step is performed prior to the forming step.

In one aspect, the method further comprises the step of converting thecarboxyl functionality to a carboxylic acid. In a further aspect, thecarboxyl functionality is an ester moiety.

In one aspect, the halide is Br, I, or pseudohalide.

In one aspect, the amine is an optionally substituted primary amine oran optionally substituted secondary amine. In a further aspect, theamine is an optionally substituted cyclic amine.

In one aspect, the coupling step is palladium-catalyzed cross-coupling.

In one aspect, the forming step is performed with PS-carbodiimide and1-hydroxybenzotriazole.

In one aspect, the aryl halide has a structure represented by a formula:

wherein R is optionally substituted alkyl; and wherein R³ comprises foursubstituents independently selected from hydrogen, halogen, andoptionally substituted alkyl.

In one aspect, the cycloalkylacetylene has a structure represented by aformula:

wherein Z comprises from zero to two carbons; and wherein R⁴ comprisesnine to thirteen substituents independently selected from hydrogen,halogen, and optionally substituted alkyl.

It is understood that the method can be used to provide the disclosedcompounds.

3. Styrylbenzamide Derivatives

In one aspect, the invention relates to a method for preparing astyrylbenzamide derivative comprising the steps of coupling a styrylbornonic acid or a styryl boronic ester with an aryl halide, wherein oneof the styryl bornonic acid or styryl boronic ester or the aryl halidebears a carboxyl functionality; and forming an amide derivative of thecarboxyl functionality by reaction with an amine. Typically, a methodinvolves a coupling reaction (e.g., transition metal catalyzed crosscoupling reaction) and a reaction forming an amide moiety. Such a methodcan be represented in the following schematic:

In a further aspect, the method can be represented in the followingschematic, which illustrates a synthetic method useful for preparationof larger amounts of the disclosed compounds:

In one aspect, the coupling step is performed prior to the forming step.

In one aspect, the method further comprises the step of converting thecarboxyl functionality to a carboxylic acid. In one aspect, the carboxylfunctionality is an ester moiety.

In a further aspect, the aryl halide bears the carboxyl functionality.

In one aspect, the halide is Br, I, or pseudohalide.

In one aspect, the amine is an optionally substituted primary amine oran optionally substituted secondary amine. In a further aspect, theamine is an optionally substituted cyclic amine.

In one aspect, the coupling step is palladium-catalyzed cross-coupling.

In one aspect, the forming step is performed with PS-carbodiimide and1-hydroxybenzotriazole.

In one aspect, the aryl halide has a structure represented by a formula:

wherein R is optionally substituted alkyl; and wherein R³ comprises foursubstituents independently selected from hydrogen, halogen, andoptionally substituted alkyl.

In one aspect, the styryl bornonic acid or styryl boronic ester has astructure represented by a formula:

wherein R is H or optionally substituted alkyl; and wherein R⁴ comprisesfive substituents independently selected from hydrogen, halogen, andoptionally substituted alkyl.

It is understood that the method can be used to provide the disclosedcompounds.

4. 4-(3-Phenyl-1,2,4-oxadiazol-5-yl)benzamide derivatives

In one aspect, the invention relates to a method for preparing a4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzamide derivative comprising thesteps of condensing an N′-hydroxybenzimidamide with an aryl carboxylicacid, wherein one of the N′-hydroxybenzimidamide or the aryl carboxylicacid bears an ester functionality; and forming an amide derivative ofthe ester functionality by reaction with an amine. Typically, a methodinvolves a condensing reaction (e.g., formation of an oxadiazol) and areaction forming an amide moiety. Such a method can be represented inthe following schematic:

In one aspect, the condensing step is performed prior to the formingstep.

In one aspect, the method further comprises the step of converting theester functionality to a carboxylic acid. In a further aspect, the arylcarboxylic acid bears the ester functionality.

In one aspect, the amine is an optionally substituted primary amine oran optionally substituted secondary amine. In a further aspect, theamine is an optionally substituted cyclic amine.

In one aspect, one or both of the condensing step and the forming stepis performed with 1-ethyl-3-[3-dimethylaminopropyl]carbodiimidehydrochloride and 1-hydroxybenzotriazole.

In one aspect, the aryl carboxylic acid has a structure represented by aformula:

wherein R is optionally substituted alkyl; and wherein R³ comprises foursubstituents independently selected from hydrogen, halogen, andoptionally substituted alkyl.

In one aspect, the N′-hydroxybenzimidamide has a structure representedby a formula:

wherein R⁴ comprises five substituents independently selected fromhydrogen, halogen, and optionally substituted alkyl.

It is understood that the method can be used to provide the disclosedcompounds.

5. 4-(Pyridinylethynyl)benzamide derivatives

In one aspect, the invention relates to a method for preparing a4-(pyridinylethynyl)benzamide derivative comprising the steps ofcoupling an arylacetylene with an aryl halide, wherein one of thearylacetylene or the aryl halide bears a carboxyl functionality; andforming an amide derivative of the carboxyl functionality by reactionwith an amine. Typically, a method involves a coupling reaction (e.g.,transition metal catalyzed cross coupling reaction) and a reactionforming an amide moiety. Such a method can be represented in thefollowing schematic:

In one aspect, the coupling step is performed prior to the forming step.

In one aspect, the method further comprises the step of converting thecarboxyl functionality to a carboxylic acid. In one aspect, the carboxylfunctionality is an ester moiety.

In a further aspect, the aryl halide bears the carboxyl functionality.

In one aspect, the halide is Br, I, or pseudohalide.

In one aspect, the amine is an optionally substituted primary amine oran optionally substituted secondary amine. In a further aspect, theamine is an optionally substituted cyclic amine.

In one aspect, the coupling step is palladium-catalyzed cross-coupling.

In one aspect, the forming step is performed with PS-carbodiimide and1-hydroxybenzotriazole.

In one aspect, the aryl halide has a structure represented by a formula:

wherein R is optionally substituted alkyl; and wherein R³ comprises foursubstituents independently selected from hydrogen, halogen, andoptionally substituted alkyl.

In one aspect, the arylacetylene has a structure represented by aformula:

wherein R⁴ comprises four substituents independently selected fromhydrogen, halogen, and optionally substituted alkyl.

It is understood that the method can be used to provide the disclosedcompounds.

6. N¹-Phenylterephthalamide derivatives

In one aspect, in the invention relates to a method for preparing aN¹-phenylterephthalamide derivative comprising the steps of reacting ananiline compound with a benzoic acid compound, wherein the benzoic acidcompound bears a carboxyl functionality; and forming an amide derivativeof the carboxyl functionality by reaction with an amine. Typically, amethod involves two separate reactions forming amide moieties. Such amethod can be represented in the following schematic:

In one aspect, the reacting step is performed prior to the forming step.

In one aspect, the method further comprises the step of converting thecarboxyl functionality to a carboxylic acid. In a further aspect, thecarboxyl functionality is an ester moiety.

In one aspect, the amine is an optionally substituted primary amine oran optionally substituted secondary amine. In a further aspect, theamine is an optionally substituted cyclic amine.

In one aspect, the reacting step is performed with1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride and1-hydroxybenzotriazole.

In one aspect, the forming step is performed with1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride and1-hydroxybenzotriazole.

In one aspect, the benzoic acid compound has a structure represented bya formula:

wherein R is optionally substituted alkyl; and wherein R³ comprises foursubstituents independently selected from hydrogen, halogen, andoptionally substituted alkyl.

In one aspect, the aniline compound has a structure represented by aformula:

wherein R is H or optionally substituted alkyl; and wherein R⁴ comprisesfive substituents independently selected from hydrogen, halogen, andoptionally substituted alkyl.

It is understood that the method can be used to provide the disclosedcompounds.

F. PHARMACEUTICAL COMPOSITIONS

In one aspect, the invention relates to pharmaceutical compositionscomprising the disclosed compounds. For example, the compositions cancomprise one or more phenylethynylbenzamide derivatives,cycloalkylethynylbenzamide derivatives, styrylbenzamide derivatives,4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzamide derivatives,4-(pyridinylethynyl)benzamide derivatives, and/orN¹-phenylterephthalamide derivatives.

In a further aspect, a pharmaceutical composition comprises atherapeutically effective amount of at least one disclosed compound anda pharmaceutically acceptable carrier. In a further aspect, apharmaceutical composition comprises a therapeutically effective amountof at least one product of a disclosed method and a pharmaceuticallyacceptable carrier. In a further aspect, a pharmaceutical compositioncomprising a therapeutically effective amount of at least onephenylethynylbenzamide derivative and a pharmaceutically acceptablecarrier. In a further aspect, a pharmaceutical composition comprises atherapeutically effective amount of at least onecycloalkylethynylbenzamide derivative and a pharmaceutically acceptablecarrier. In a further aspect, a pharmaceutical composition comprises atherapeutically effective amount of at least one styrylbenzamidederivative and a pharmaceutically acceptable carrier. In a furtheraspect, a pharmaceutical composition comprises a therapeuticallyeffective amount of at least one4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzamide derivative and apharmaceutically acceptable carrier. In a further aspect, apharmaceutical composition comprises a therapeutically effective amountof at least one 4-(pyridinylethynyl)benzamide derivative and apharmaceutically acceptable carrier. In a further aspect, apharmaceutical composition comprises a therapeutically effective amountof at least one N¹-phenylterephthalamide derivative and apharmaceutically acceptable carrier.

In certain aspects, the disclosed pharmaceutical compositions comprisethe disclosed compounds (including pharmaceutically acceptable salt(s)thereof) as an active ingredient, a pharmaceutically acceptable carrier,and, optionally, other therapeutic ingredients or adjuvants. The instantcompositions include those suitable for oral, rectal, topical, andparenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions can be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts prepared from pharmaceutically acceptable non-toxic bases oracids. When the compound of the present invention is acidic, itscorresponding salt can be conveniently prepared from pharmaceuticallyacceptable non-toxic bases, including inorganic bases and organic bases.Salts derived from such inorganic bases include aluminum, ammonium,calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium,manganese (-ic and -ous), potassium, sodium, zinc and the like salts.Particularly preferred are the ammonium, calcium, magnesium, potassiumand sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, as well as cyclic amines and substituted amines such asnaturally occurring and synthesized substituted amines. Otherpharmaceutically acceptable organic non-toxic bases from which salts canbe formed include ion exchange resins such as, for example, arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

As used herein, the term “pharmaceutically acceptable non-toxic acids”,includes inorganic acids, organic acids, and salts prepared therefrom,for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

In practice, the compounds of the invention, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier can take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compounds of theinvention, and/or pharmaceutically acceptable salt(s) thereof, can alsobe administered by controlled release means and/or delivery devices. Thecompositions can be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention can include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of the compounds of the invention. The compounds of theinvention, or pharmaceutically acceptable salts thereof, can also beincluded in pharmaceutical compositions in combination with one or moreother therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likecan be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like can be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets can be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets can be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions of the present invention suitable forparenteral administration can be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, mouth washes, gargles and the like.Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared, utilizing acompound of the invention, or pharmaceutically acceptable salts thereof,via conventional processing methods. As an example, a cream or ointmentis prepared by mixing hydrophilic material and water, together withabout 5 wt % to about 10 wt % of the compound, to produce a cream orointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories can be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above can include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, and/or pharmaceuticallyacceptable salts thereof, can also be prepared in powder or liquidconcentrate form.

A potentiated amount of an mGluR agonist to be administered incombination with an effective amount of a compound of formula I isexpected to vary from about 0.1 milligram per kilogram of body weightper day (mg/kg/day) to about 100 mg/kg/day and is expected to be lessthan the amount that is required to provide the same effect whenadministered without an effective amount of a disclosed compound.Preferred amounts of a co-administered mGluR agonist are able to bedetermined by one skilled in the art.

The present invention is further directed to a method for themanufacture of a medicament for poteniating glutamate receptor activity(e.g., treatment of one or more neurological and/or psychiatric disorderassociated with glutamate dysfunction) in mammals (e.g., humans)comprising combining a compound of the present invention with apharmaceutically acceptable carrier or diluent.

Thus, in one aspect, the invention relates to pharmaceuticalcompositions comprising the disclosed compounds. That is, apharmaceutical composition can be provided comprising a therapeuticallyeffective amount of at least one disclosed compound or at least oneproduct of a disclosed method and a pharmaceutically acceptable carrier.

The disclosed pharmaceutical compositions can further comprise othertherapeutically active compounds, which are usually applied in thetreatment of the above mentioned pathological conditions. For example,the disclosed compounds and compositions can be coadministered with oneor more antipsychotic agents. In one aspect, an antipsychotic agent canbe any compound that has been shown to be useful or is believed to beuseful in treating at least a positive symptom of schizophrenia.

Antipsychotic agents useful in treating at least a positive symptom ofschizophrenia include typical antipsychotic agents, atypicalantipsychotic agents, and other antipsychotic agents that may or may notbe classified as typical or atypical antipsychotic agents. In certainembodiments, an antipsychotic agent is a typical antipsychotic agent. Incertain embodiments, an antipsychotic agent is a dopamine D2 receptorantagonist, which may be a selective dopamine D2 receptor antagonist ora partial dopamine D2 receptor antagonist. Typical antipsychotic agentsare generally recognized as selective dopamine D2 receptor antagonists.

Antipsychotic agents useful in treating positive symptoms ofschizophrenia include, but are not limited to, acetophenazine,alseroxylon, amitriptyline, aripiprazole, astemizole, benzquinamide,carphenazine, chlormezanone, chlorpromazine, chlorprothixene, clozapine,desipramine, droperidol, aloperidol, fluphenazine, flupenthixol,glycine, oxapine, mesoridazine, molindone, olanzapine, ondansetron,perphenazine, pimozide, prochlorperazine, procyclidine, promazine,propiomazine, quetiapine, remoxipride, reserpine, risperidone,sertindole, sulpiride, terfenadine, thiethylperzaine, thioridazine,thiothixene, trifluoperazine, triflupromazine, trimeprazine, andziprasidone. Examples of typical antipsychotic agents useful fortreating positive symptoms of schizophrenia include acetophenazine,chlorpromazine, chlorprothixene, droperidol, fluphenazine, haloperidol,loxapine, mesoridazine, methotrimeprazine, molindone, perphenazine,pimozide, raclopride, remoxipride, thioridazine, thiothixene, andtrifluoperazine. Examples of atypical antipsychotic agents useful fortreating positive symptoms of schizophrenia include aripiprazole,clozapine, olanzapine, quetiapine, risperidone, sertindole, andziprasidone.

Other antipsychotic agents useful for treating positive symptoms ofschizophrenia include amisulpride, balaperidone, blonanserin,butaperazine, carphenazine, eplavanserin, iloperidone, lamictal,onsanetant, paliperidone, perospirone, piperacetazine, raclopride,remoxipride, sarizotan, sonepiprazole, sulpiride, ziprasidone, andzotepine; serotonin and dopamine (5HT/D2) agonists such as asenapine andbifeprunox; neurokinin 3 antagonists such as talnetant and osanetant;AMPAkines such as CX-516, galantamine, memantine, modafinil,ocaperidone, and tolcapone; and .alpha.-amino acids such as D-serine,D-alanine, D-cycloserine, and N-methylglycine. Thus, antipsychoticagents include typical antipsychotic agents, atypical antipsychoticagents, and other compounds useful for treating schizophrenia in apatient, and particularly useful for treating the positive symptoms ofschizophrenia.

Thus, in one aspect, the invention also relates to methods ofcoadminstering to a mammal at least one disclosed compound and one ormore other therapeutically active compounds, which are usually appliedin the treatment of the above mentioned pathological conditions. Forexample, the disclosed methods can relate to coadministration oftherapeutically effective amounts of one or more disclosed compound withone or more antipsychotic agents.

In a further aspect, the invention also relates to kits comprising atleast one disclosed compound and one or more other therapeuticallyactive compounds, which are usually applied in the treatment of theabove mentioned pathological conditions. For example, the disclosed kitscan comprise therapeutically effective amounts of one or more disclosedcompound and one or more antipsychotic agents. The kits can beco-packaged, co-formulated, and/or co-delivered with the antipsychoticagents. For example, a drug manufacturer, a drug reseller, a physician,or a pharmacist can provide a disclosed kit for delivery to a patient.

In the treatment conditions which require potentiation of metabotropicglutamate receptor activity an appropriate dosage level will generallybe about 0.01 to 500 mg per kg patient body weight per day and can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day; more preferably 0.5 to 100mg/kg per day. A suitable dosage level can be about 0.01 to 250 mg/kgper day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg perday. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0to 50 mg/kg per day. For oral administration, the compositions arepreferably provided in the from of tablets containing 1.0 to 1000miligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20,25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and1000 milligrams of the active ingredient for the symptomatic adjustmentof the dosage of the patient to be treated. The compound can beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day. This dosing regimen can be adjusted to provide theoptimal therapeutic response.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors. Such factorsinclude the age, body weight, general health, sex, and diet of thepatient. Other factors include the time and route of administration,rate of excretion, drug combination, and the type and severity of theparticular disease undergoing therapy.

It is understood that the disclosed compositions can be employed in thedisclosed methods of using.

G. METHODS OF USING THE COMPOUNDS AND COMPOSITIONS

The amino acid L-glutamate (referred to herein simply as glutamate) isthe principal excitatory neurotransmitter in the mammalian centralnervous system (CNS). Within the CNS, glutamate plays a key role insynaptic plasticity (e.g., long term potentiation (the basis of learningand memory)), motor control and sensory perception. It is now wellunderstood that a variety of neurological and psychiatric disorders,including, but not limited to, schizophrenia general psychosis andcognitive deficits, are associated with dysfunctions in theglutamatergic system. Thus, modulation of the glutamatergic system is animportant therapeutic goal. Glutamate acts through two distinctreceptors: ionotropic and metabotropic glutamate receptors. The firstclass, the ionotropic glutamate receptors, are multi-subunitligand-gated ion channels that mediate excitatory post-synapticcurrents. Three subtypes of ionotropic glutamate receptors have beenidentified, and despite glutamate serving as agonist for all threereceptor subtypes, selective ligands have been discovered that activateeach subtype. The ionotropic glutamate receptors are named after theirrespective selective ligands: kainite receptors, AMPA receptors and NMDAreceptors.

The second class of glutamate receptor, termed metabotropic glutamatereceptors, (mGluRs), are G-protein coupled receptors (GPCRs) thatmodulate neurotransmitter release or the strength of synaptictransmission, based on their location (pre- or post-synaptic). ThemGluRs are family C GPCR, characterized by a large (˜560 amino acid)“venus fly trap” agonist binding domain in the amino-terminal domain ofthe receptor. This unique agonist binding domain distinguishes family CGPCRs from family A and B GPCRs wherein the agonist binding domains arelocated within the 7-strand transmembrane spanning (7TM) region orwithin the extracellular loops that connect the strands to this region.To date, eight distinct mGluRs have been identified, cloned andsequenced. Based on structural similarity, primary coupling tointracellular signaling pathways and pharmacology, the mGluRs have beenassigned to three groups: Group I (mGluR1 and mGluR5), Group II (mGluR2and mGluR3) and Group III (mGluR4, mGluR6, mGluR7 and mGluR8). Group ImGluRs are coupled through Gαq/11 to increase inositol phosphate andmetabolism and resultant increases in intracellular calcium. Group ImGluRs are primarily located post-synaptically and have a modulatoryeffect on ion channel activity and neuronal excitability. Group II(mGluR2 and mGluR3) and Group III (mGluR4, mGluR6, mGluR7 and mGluR8)mGluRs are primarily located pre-synaptically where they regulate therelease of neurotransmitters, such as glutamate. Group II and Group IIImGluRs are coupled to G□i and its associated effectors such as adenylatecyclase.

Post-synaptic mGluRs are known to functionally interact withpost-synaptic ionotropic glutamate receptors, such as the NMDA receptor.For example, activation of mGluR5 by a selective agonist has been shownto increase post-synaptic NMDA currents (Mannaioni et. al. J. Neurosci.21:5925-5934 (2001)). Therefore, modulation of mGluRs is an approach tomodulating glutamatergic transmission. Numerous reports indicate thatmGluR5 plays a role in a number of disease states including anxiety(Spooren et. al. J. Pharmacol. Exp. Therapeut. 295:1267-1275 (2000),Tatarczynska et al. Br. J. Pharmaol. 132:1423-1430 (2001)),schizophrenia (reviewed in Chavez-Noriega et al. Curr. Drug Targets: CNS& Neurological Disorders 1:261-281 (2002), Kinney, G. G. et al. J.Pharmacol. Exp. Therapeut. 313:199-206 (2005), addiction to cocaine(Chiamulera et al. Nature Neurosci. 4:873-874 (2001), Parkinson'sdisease (Awad et al. J. Neurosci. 20:7871-7879 (2000), Ossowska et al.Neuropharmacol. 41: 413-420 (2001) and pain (Salt and Binns Neurosci.100:375-380 (2001).

In some aspects, the mGluR of the disclosed methods is a type I mGluR.In some aspects, the mGluR of the disclosed methods is mGluR5.

1. Treatment Methods

The compounds disclosed herein are useful for treating, preventing,ameliorating, controlling or reducing the risk of a variety ofneurological and psychiatric disorders associated with glutamatedysfunction. Thus, provided is a method of treating or preventing adisorder in a subject comprising the step of administering to thesubject at least one disclosed compound; at least one disclosedpharmaceutical composition; and/or at least one disclosed product in adosage and amount effective to treat the disorder in the subject.

Also provided is a method for the treatment of one or more neurologicaland/or psychiatric disorders associated with glutamate dysfunction in asubject comprising the step of administering to the subject at least onedisclosed compound; at least one disclosed pharmaceutical composition;and/or at least one disclosed product in a dosage and amount effectiveto treat the disorder in the subject.

Examples of disorders associated with glutamate dysfunction include:acute and chronic neurological and psychiatric disorders such ascerebral deficits subsequent to cardiac bypass surgery and grafting,stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatalhypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia(including AIDS-induced dementia), Alzheimer's disease, Huntington'sChorea, amyotrophic lateral sclerosis, ocular damage, retinopathy,cognitive disorders, idiopathic and drug-induced Parkinson's disease,muscular spasms and disorders associated with muscular spasticityincluding tremors, epilepsy, convulsions, migraine (including migraineheadache), urinary incontinence, substance tolerance, addictivebehavior, including addiction to substances (including opiates,nicotine, tobacco products, alcohol, benzodiazepines, cocaine,sedatives, hypnotics, etc.), withdrawal from such addictive substances(including substances such as opiates, nicotine, tobacco products,alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), obesity,psychosis, schizophrenia, anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder), mooddisorders (including depression, mania, bipolar disorders), trigeminalneuralgia, hearing loss, tinnitus, macular degeneration of the eye,emesis, brain edema, pain (including acute and chronic pain states,severe pain, intractable pain, neuropathic pain, and post-traumaticpain), tardive dyskinesia, sleep disorders (including narcolepsy),attention deficit/hyperactivity disorder, and conduct disorder.

Anxiety disorders that can be treated or prevented by the compositionsdisclosed herein include generalized anxiety disorder, panic disorder,and obsessive compulsive disorder. Addictive behaviors include addictionto substances (including opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), withdrawal fromsuch addictive substances (including substances such as opiates,nicotine, tobacco products, alcohol, benzodiazepines, cocaine,sedatives, hypnotics, etc.) and substance tolerance.

Thus, in some aspects of the disclosed method, the disorder is dementia,delirium, amnestic disorders, age-related cognitive decline,schizophrenia, psychosis including schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder, substance-related disorder, movement disorders, epilepsy,chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders,brain edema, sleep disorder, narcolepsy, anxiety, affective disorder,panic attacks, unipolar depression, bipolar disorder, psychoticdepression.

Thus, provided is a method for treating or prevention schizophrenia,comprising: administering to a subject at least one disclosed compound;at least one disclosed pharmaceutical composition; and/or at least onedisclosed product in a dosage and amount effective to treat the disorderin the subject. At present, the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV) (1994, AmericanPsychiatric Association, Washington, D.C.), provides a diagnostic toolincluding schizophrenia and related disorders.

Also provided is a method for treating or prevention anxiety,comprising: administering to a subject at least one disclosed compound;at least one disclosed pharmaceutical composition; and/or at least onedisclosed product in a dosage and amount effective to treat the disorderin the subject. At present, the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV) (1994, AmericanPsychiatric Association, Washington, D.C.), provides a diagnostic toolincluding anxiety and related disorders. These include: panic disorderwith or without agoraphobia, agoraphobia without history of panicdisorder, specific phobia, social phobia, obsessive-compulsive disorder,post-traumatic stress disorder, acute stress disorder, generalizedanxiety disorder, anxiety disorder due to a general medical condition,substance-induced anxiety disorder and anxiety disorder not otherwisespecified.

a. Potentiation of Metabotropic Glutamate Receptor Activity

In one aspect, the invention relates to a method for potentiation ofmetabotropic glutamate receptor activity in a mammal comprising the stepof administering to the mammal at least one compound having a structurerepresented by a formula:

wherein

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R¹and R² are independently hydrogen or an optionally substituted organicradical comprising from 1 to 12 carbon atoms; wherein R⁰ is anoptionally substituted organic radical comprising 4 to 14 carbon atoms;and wherein L is an organic divalent radical comprising 1 to 7 carbonatoms and is selected from:

wherein R^(7a) and R^(7b) together form an optionally substitutedcarbocyclic or heterocyclic ring having from two to five carbons or areindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, amino, and an organic radical comprising 1 to 5 carbon atomsselected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl orC2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; or a pharmaceutically acceptable salt orN-oxide thereof, in a dosage and amount effective to potentiatemetabotropic glutamate receptor activity in the mammal.

In one aspect, the mammal is a human. In a further aspect, the methodfurther comprises identifying a mammal with a need for potentiation ofmetabotropic glutamate receptor activity. In a further aspect, themammal has a need for potentiation of metabotropic glutamate receptoractivity prior to administration. In a further aspect, the mammal hasbeen diagnosed with a need for potentiation of metabotropic glutamatereceptor activity prior to administration.

b. Partial Agonism of Metabotropic Glutamate Receptor Activity

In one aspect, the invention relates to a method for partial agonism ofmetabotropic glutamate receptor activity in a mammal comprising the stepof administering to the mammal at least one compound having a structurerepresented by a formula:

wherein each

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R¹and R² are independently hydrogen or an optionally substituted organicradical comprising from 1 to 12 carbon atoms; wherein R⁰ is anoptionally substituted organic radical comprising 4 to 14 carbon atoms,wherein L is an organic divalent radical comprising 1 to 7 carbon atomsand is selected from:

wherein R^(7a) and R^(7b) together form an optionally substitutedcarbocyclic or heterocyclic ring having from two to five carbons or areindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, amino, and an organic radical comprising 1 to 5 carbon atomsselected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl orC2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; or a pharmaceutically acceptable salt orN-oxide thereof, in a dosage and amount effective to exhibit partialagonism of metabotropic glutamate receptor activity in the mammal.

In one aspect, Y¹ is selected from N and C—R⁴. In a further aspect, Y²is selected from N and C—H. In a further aspect, each R^(3a) and R^(3b)is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol,amino, or an organic radical comprising 1 to 6 carbon atoms. In afurther aspect, R⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol,or an organic radical comprising 1 to 12 carbon atoms.

In a further aspect, L is an organic divalent radical comprising 1 to 7carbon atoms and is selected from:

wherein R^(7a) and R^(7b) together form an optionally substitutedcarbocyclic or heterocyclic ring having from two to five carbons or areindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, amino, and an organic radical comprising 1 to 5 carbon atomsselected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl orC2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; and wherein R⁸ is selected from hydrogen, andan organic radical comprising 1 to 6 carbon atoms selected fromoptionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl,optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl,optionally substituted aryl, and optionally substituted heteroaryl.

In one aspect, the mammal is a human. In a further aspect, the methodfurther comprises identifying a mammal with a need for partial agonismof metabotropic glutamate receptor activity. In a further aspect, themammal has a need for partial agonism of metabotropic glutamate receptoractivity prior to administration. In a further aspect, the mammal hasbeen diagnosed with a need for partial agonism of metabotropic glutamatereceptor activity prior to administration.

c. Treatment of a Disorder in a Mammal

In one aspect, the invention relates to a method for the treatment of aneurological and/or psychiatric disorder associated with glutamatedysfunction in a mammal comprising the step of administering to themammal at least one compound having a structure represented by aformula:

wherein

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R¹and R² are independently hydrogen or an optionally substituted organicradical comprising from 1 to 12 carbon atoms; wherein R⁰ is anoptionally substituted organic radical comprising 4 to 14 carbon atoms,wherein L is an organic divalent radical comprising 1 to 7 carbon atomsand is selected from:

wherein R^(7a) and R^(7b) together form an optionally substitutedcarbocyclic or heterocyclic ring having from two to five carbons or areindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, amino, and an organic radical comprising 1 to 5 carbon atomsselected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl orC2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; and wherein R⁸ is selected from hydrogen, andan organic radical comprising 1 to 6 carbon atoms selected fromoptionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl,optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl,optionally substituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt or N-oxide thereof, in a dosage andamount effective to treat the neurological and/or psychiatric disorderassociated with glutamate dysfunction in the mammal.

In one aspect, the mammal is a human. In a further aspect, the methodfurther comprises identifying a mammal with a need for treatment of thedisorder. In a further aspect, the mammal has a need for treatment ofthe disorder prior to administration. In a further aspect, the mammalhas been diagnosed with a need for treatment of the disorder prior toadministration.

In one aspect, the disorder is one or more neurological and/orpsychiatric disorder associated with glutamate dysfunction in themammal. For example, the disorder can be one or more of dementia,delirium, amnestic disorders, age-related cognitive decline,schizophrenia, psychosis including schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder, substance-related disorder, movement disorders, epilepsy,chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders,brain edema, sleep disorder, narcolepsy, anxiety, affective disorder,panic attacks, unipolar depression, bipolar disorder, and psychoticdepression.

In a further aspect, Y¹ is selected from N and C—R⁴. In a furtheraspect, Y² is selected from N and C—H. In a further aspect, each R^(3a)and R^(3b) is independently hydrogen, halogen, hydroxyl, cyano, nitro,thiol, amino, or an organic radical comprising 1 to 6 carbon atoms. In afurther aspect, R⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol,or an organic radical comprising 1 to 12 carbon atoms.

In a further aspect, L is an organic divalent radical comprising 1 to 7carbon atoms and is selected from:

In a further aspect, R^(7a) and R^(7b) together form an optionallysubstituted carbocyclic or heterocyclic ring having from two to fivecarbons or are independently selected from hydrogen, halogen, hydroxyl,cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl orC2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl.

In a further aspect, R⁸ is selected from hydrogen, and an organicradical comprising 1 to 6 carbon atoms selected from optionallysubstituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionallysubstituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl,optionally substituted aryl, and optionally substituted heteroaryl.

In a further aspect, the disorder is a neurological and/or psychiatricdisorder associated with glutamate dysfunction. In a further aspect, thedisorder is selected from dementia, delirium, amnestic disorders,age-related cognitive decline, schizophrenia, psychosis includingschizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, substance-relateddisorder, movement disorders, epilepsy, chorea, pain, migraine,diabetes, dystonia, obesity, eating disorders, brain edema, sleepdisorder, narcolepsy, anxiety, affective disorder, panic attacks,unipolar depression, bipolar disorder, and psychotic depression.

In one aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for treatment of the disorder prior tothe administering step.

d. Enhancing Cognition

Schizophrenia symptoms can be classified as positive, negative, orcognitive. Positive symptoms of schizophrenia include delusion andhallucination, which can be measured using, for example, the Positiveand Negative Syndrome Scale (PANSS) (see Kay et al., 1987, SchizophreniaBulletin 13, 261-276). Negative symptoms of schizophrenia include affectblunting, anergia, alogia, and social withdrawal, which can be measuredfor example, using the Scales for the Assessment of Negative Symptoms(SANS) (see Andreasen, 1983, Scales for the Assessment of NegativeSymptoms, Iowa City, Iowa). Cognitive symptoms of schizophrenia includeimpairment in obtaining, organizing, and using intellectual knowledgewhich can be measured using the Positive and Negative SyndromeScale-cognitive subscale (PANSS-cognitive subscale) (Lindenmayer et al.,J Nerv Ment Dis 1994, 182, 631-638) or by assessing the ability toperform cognitive tasks such as, for example, using the Wisconsin CardSorting Test (see, e.g., Green et al., Am J Psychiatry 1992, 149,162-67; and Koren et al., Schizophr Bull 2006, 32(2), 310-26).

In one aspect, the invention relates to a method for enhancing cognitionin a mammal comprising the step of administering to the mammal at leastone compound having a structure represented by a formula:

wherein each

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R¹and R² are independently hydrogen or an optionally substituted organicradical comprising from 1 to 12 carbon atoms; wherein R⁰ is anoptionally substituted organic radical comprising 4 to 14 carbon atoms,wherein L is an organic divalent radical comprising 1 to 7 carbon atomsand is selected from:

wherein R^(7a) and R^(7b) together form an optionally substitutedcarbocyclic or heterocyclic ring having from two to five carbons or areindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, amino, and an organic radical comprising 1 to 5 carbon atomsselected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl orC2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; or a pharmaceutically acceptable salt orN-oxide thereof, in a dosage and amount effective to enhance cognitionin the mammal.

In one aspect, the mammal is a human. In a further aspect, the methodfurther comprises identifying a mammal with a need for enhancingcognition. In a further aspect, the mammal has a need for enhancingcognition prior to administration. In a further aspect, the mammal hasbeen diagnosed with a need for enhancing cognition prior toadministration.

In a further aspect, the cognition enhancement is a statisticallysignificant increase in Novel Object Recognition. In a further aspect,the cognition enhancement is a statistically significant increase insynaptic plasticity. In a further aspect, the cognition enhancement is astatistically significant increase in performance of the Wisconsin CardSorting Test.

mGluR5 potentiation has also been linked to improvement of cognition(Kinney, G. G.; O'Brien, Lemaire, W.; Burno, M.' Bickel, D. J.;Clements, M. K.; Wisnoski, D. D.; Lindsley, C. W.; Tiller, P. R.; Smith,S.; Jacobson, M. A.; Sur, C.; Duggan, M. E.; Pettibone, D. J.; Williams,Jr., D. W. ‘A novel selective allosteric modulator of metabotropicglutamate receptor subtype 5 (mGluR5) has an antipsychotic profile inrat behavioral models’ J. Pharmacol. Exp. Therapeut. 2005, 313(1), 199;Lindsley, C. W.; Wisnoski, D. D.; Leister, W. H.; O'Brien, J. A.;Lemiare, W.; Williams, Jr., D. L.; Burno, M.; Sur, C.; Kinney, G. G.;Pettibone, D. J.; iller, P. R.; Smith, S.; Duggan, M. E.; Hartman, G.D.; Conn, P. J.; Huff, J. R. ‘Discovery of positive allostericmodulators for the metabotropic glutamate receptor subtype from a seriesof N-(1,3-Diphenyl-1H-pyrazol-5-yl)benzamides that potentiate receptorfunction in vivo’ J. Med. Chem. 2004, 47, 5825; Epping-Jordan M. P.,Nayak, S., Derouet, F., Dominguez, H., Bessis A. S., Le Poul E., LudwigB. L. Mutel V., Poli S. M. and Rocher J. P. In Vivo Characterization ofmGluR5 Positive Allosteric Modulators as Novel Treatments forSchizophrenia and Cognitive Dysfunction Neuropharmacology 2005, 49,243.). This theory was validated in a cellular model of the long lastingchanges in transmission of synaptic transmission that are thought tounderlie multiple forms of learning and memory. This model is termedhippocampal long term potentiation (LTP) and involves measurements ofstrengthen in synaptic connections between neurons in the brain that arecritical for learning to occur. FIG. 17 shows the increase in strengthof synaptic connections after applying a stimulus to the synapse in theabsence and presence of two structurally distinct mGluR5 PAMs, VU29 (toppanel) and ADX47273 (bottom panel). Both PAMs induced a robust increasein synaptic connections in a manner that would be predicted to enhancelearning and memory. This could provide an approach to improvingcognition in disorders involving impaired cognitive function, includingschizophrenia, Alzheimers disease, Parkinson's disease, and multipleother human brain disorders. A representative mGluR5 PAM that enhanceshippocampal LTP is also active in preclinical cognition model of NovelObject Recognition (NOR) wherein the mGluR5 PAM, ADX47273, displaying arobust and significant improvement in NOR, equivalent to the knowncognitive enhancing H3 antagonist Thioperide (FIG. 11).

2. Manufacture of a Medicament

Also provided is a method for the manufacture of a medicament fortreatment of a disorder in a mammal, for partial agonism of metabotropicglutamate receptor activity in a mammal, for enhancing cognition in amammal, and/or for potentiation of metabotropic glutamate receptoractivity in a mammal comprising combining at least one compound having astructure:

wherein

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R¹and R² are independently hydrogen or an optionally substituted organicradical comprising from 1 to 12 carbon atoms; wherein R⁰ is anoptionally substituted organic radical comprising 4 to 14 carbon atoms;and wherein L is an organic divalent radical comprising 1 to 7 carbonatoms and is selected from:

wherein R^(7a) and R^(7b) together form an optionally substitutedcarbocyclic or heterocyclic ring having from two to five carbons or areindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, amino, and an organic radical comprising 1 to 5 carbon atomsselected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl orC2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; or a pharmaceutically acceptable salt orN-oxide thereof, with a pharmaceutically acceptable carrier.

3. Use of Compounds

Also provided are uses of the disclosed compounds. For example, providedis the use of a compound having a structure:

wherein

is an optional covalent bond; wherein Y¹ and Y² are independentlyselected from N and C—R; wherein R comprises two to four substituentsindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R¹and R² are independently hydrogen or an optionally substituted organicradical comprising from 1 to 12 carbon atoms; wherein R⁰ is anoptionally substituted organic radical comprising 4 to 14 carbon atoms;and wherein L is an organic divalent radical comprising 1 to 7 carbonatoms and is selected from:

wherein R^(7a) and R^(7b) together form an optionally substitutedcarbocyclic or heterocyclic ring having from two to five carbons or areindependently selected from hydrogen, halogen, hydroxyl, cyano, nitro,thiol, amino, and an organic radical comprising 1 to 5 carbon atomsselected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl orC2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted thioalkyl, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, and optionally substituted amino,thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl,and alkylamine-carbonyl; or a pharmaceutically acceptable salt orN-oxide thereof.

In one aspect, the use is characterized in that the mammal is a human.

In one aspect, the use relates to a treatment of a disorder in a mammal.

In one aspect, the use is characterized in that the disorder is aneurological and/or psychiatric disorder associated with glutamatedysfunction.

In one aspect, the use relates to potentiation for partial agonism ofmetabotropic glutamate receptor activity in a mammal.

4. Subjects

The subject of the herein disclosed methods can be a vertebrate, such asa mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subjectof the herein disclosed methods can be a human, non-human primate,horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.The term does not denote a particular age or sex. Thus, adult andnewborn subjects, as well as fetuses, whether male or female, areintended to be covered. A patient refers to a subject afflicted with adisease or disorder. The term “patient” includes human and veterinarysubjects.

In some aspects of the disclosed methods, the subject has been diagnosedwith a need for treatment of one or more neurological and/or psychiatricdisorder associated with glutamate dysfunction prior to theadministering step.

In some aspects of the disclosed method, the subject has been diagnosedwith a need for potentiation of metabotropic glutamate receptor activityprior to the administering step.

In some aspects of the disclosed method, the subject has been diagnosedwith a need for partial agonism of metabotropic glutamate receptoractivity prior to the administering step.

H. EXPERIMENTAL

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

1. ethyl 4-(phenylethynyl)benzoate

To a solution of ethyl 4-iodobenzoate (5.0 g, 18.2 mmol) in DMF (8 mL)was added phenylacetylene (2.25 g, 22.1 mmol), Pd(Ph₃P)₄ (502 mg, 0.45mmol), CuI (172 mg, 0.91 mmol) and diethylamine (2 mL). The reactionvessel was sealed and heated at 60° C. for 1 h in a microwave reactor.The reaction was cooled to room temperature, diluted with EtOAc:hexanes(2:1, 150 mL) and washed with water (2×100 mL) and brine (100 mL). Theorganic phase was dried over MgSO₄, filtered and concentrated undervacuum. The crude product was purified by column chromatography (silicagel) using 0 to 10% EtOAc/hexanes to afford ethyl4-(phenylethynyl)benzoate (7.89 g, 86%) as a pale yellow solid; ¹H-nmr(400 MHz, CDCl₃) δ 8.05 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.56(dd, J=8.0, 2.0 Hz, 2H), 7.41-7.37 (m, 3H), 4.41 (q, J=7.0 Hz, 2H), 1.44(t, J=7.0 Hz, 3H); LC (275 nM) 5.79 min (>98%); MS (ESI) m/z=250.9.

2. 4-(phenylethynyl)benzoic acid

To a solution of ethyl 4-(phenylethynyl)benzoate (7.81 g, 31.2 mmol) inTHF (80 mL) was added MeOH (15 mL) and a solution of LiOH (5.24 g, 124mmol) in water (15 mL). The reaction was stirred at room temperature andfor 4 h. The reaction was acidified with 1 N HCl (50 mL), and4-(phenylethynyl)benzoic acid was isolated (5.78 g, 83%) as a whitesolid; ¹H-nmr (400 MHz, CDCl₃) δ 8.11 (d, J=8.0 Hz, 2H), 7.75-7.68 (m,1H), 7.64 (d, J=8.0 Hz, 2H), 7.62-7.56 (m, 2H), 7.52-7.47 (m, 1H),7.43-7.36 (m, 3H); LC (275 nM) 5.12 min (>98%); MS (ESI) m/z=222.9.

3. (4-hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone

To a solution of 4-(phenylethynyl)benzoic acid (1.40 g, 6.30 mmol) andDIPEA (2.70 g, 20.8 mmol) in DMF (25 mL) was added EDC (1.41 g, 7.56mmol), HOBt (850 mg, 6.30 mmol) and 4-hydroxypiperidine hydrochloride(1.29 g, 9.46 mmol). The reaction was stirred at room temperature for 18h. The reaction was diluted with water (100 mL) and(4-hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone was isolated(1.84 g, 98%) as a white solid by vacuum filtration; ¹H-nmr (400 MHz,CDCl₃) δ 7.58 (d, J=8.0 Hz, 2H), 7.56-7.52 (m, 2H), 7.44-7.34 (m, 5H),4.21-4.08 (m, 1H), 4.03-3.96 (m, 1H), 3.81-3.48 (m, 1H), 3.47-3.16 (m,2H), 2.08-1.79 (m, 2H), 1.71-1.42 (m, 2H); LC (275 nM) 5.01 min (>98%);MS (ESI) m/z=305.9.

4. 4-((3-fluorophenyl)ethynyl)benzoic acid

To a solution of ethyl 4-Iodobenzoate (10.0 g, 36.2 mmol) in DMF (30 mL)was added 3-fluorophenylacetylene (5.22 g, 43.4 mmol), Pd(Ph₃P)₄ (1.04g, 0.91 mmol), CuI (346 mg, 1.82 mmol) and diethylamine (6 mL). Thereaction vessel was sealed and heated at 60° C. for 1 h in a microwavereactor. The reaction was cooled to room temperature, diluted withEtOAc:hexanes (2:1, 250 mL) and washed with water (2×200 mL) and brine(200 mL). The organic phase was dried over MgSO₄, filtered andconcentrated under vacuum. The crude product was dissolved in THF (130mL) added MeOH (28 mL) and a solution of LiOH (3.04 g, 72.4 mmol) inwater (28 mL). The reaction was stirred at room temperature and for 4 h.The reaction was acidified with 1 N HCl (100 mL) and4-((3-fluorophenyl)ethynyl)benzoic acid was isolated (6.89 g, 79%) as alight tan solid; ¹H-nmr (400 MHz, d₆-DMSO) δ 7.97 (d, J=8.5 Hz, 2H),7.68 (d, J=8.5 Hz, 1H), 7.55-7.42 (m, 3H), 7.21 (td, J=8.0, 2.0 Hz, 1H);LC (290 nM) 5.27 min (>98%); MS (ESI) m/z=240.7.

5. (4-((3-fluorophenyl)ethynyl)phenyl)(morpholino)methanone

To a solution of 4-((3-fluorophenyl)ethynyl)benzoic acid (2.0 g, 8.33mmol) and DIPEA (2.38 g, 18.3 mmol) in DMF (35 mL) was added EDC (1.86g, 10.0 mmol), HOBt (1.35 g, 10.0 mmol) and morpholine (1.07 g, 12.5mmol). The reaction was stirred at room temperature for 18 h. Thereaction was diluted with water (200 mL) and extracted with EtOAc (2×150mL). The combined organic extracts were washed with water (2×100 mL) andbrine (100 mL), dried over MgSO₄, filtered and concentrated undervacuum. The residue was purified by column chromatography (silica gel)using 0 to 90% EtOAc/hexanes to afford(4-((3-fluorophenyl)ethynyl)phenyl)(morpholino)methanone (2.35 g, 89%)as a light tan solid; ¹H-nmr (400 MHz, CDCl₃) δ 7.57 (d, J=8.5 Hz, 2H),7.41 (d, J=8.5 Hz, 2H), 7.38-7.31 (m, 2H), 7.28-7.21 (m, 1H), 7.13-7.05(m, 1H), 4.00-3.31 (bd s, 8H); LC (290 nM) 5.08 min (>98%); MS (ESI)m/z=310.

6. (4((3-fluorophenyl)ethynyl)phenyl)(4-hydroxylpiperidin-1-yl-methanone

(4((3-fluorophenyl)ethynyl)phenyl)(4-hydroxylpiperidin-1-yl-methanone(2.61 g, 97%) light cream solid as prepared in identical fashion to(4((3-fluorophenyl)ethynyl)phenyl)(4-hydroxylpiperidin-1-yl-methanone;¹H-nmr (400 MHz, CDCl₃) δ 7.57 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.5 Hz,2H), 7.38-7.31 (m, 2H), 7.28-7.21 (m, 1H), 7.11-7.03 (m, 1H), 4.21-4.08(m, 1H), 4.03-3.96 (m, 1H), 3.81-3.48 (m, 1H), 3.47-3.15 (m, 2H),2.05-1.78 (m, 2H), 1.71-1.42 (m, 2H); LC (290 nM) 4.86 min (>98%); LC(290 nM) 4.93 min (>98%); MS (ESI) m/z=324.

7.(4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxymethyl)piperidin-1-yl)methanone

Amide(4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxymethyl)piperidin-1-yl)methanone(2.32 g, 78%) light cream solid as prepared in identical fashion to(4-((3-fluorophenyl)ethynyl)phenyl)(morpholino)methanone; ¹H-nmr (400MHz, CDCl₃) δ 7.56 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 7.38-7.30(m, 2H), 7.28-7.21 (m, 1H), 7.09-7.02 (m, 1H), 3.89-3.71 (m, 1H),3.61-3.52 (m, 2H), 3.12-2.71 (m, 2H), 1.96-1.69 (m, 3H), 1.41-1.12 (m,3H); LC (290 nM) 4.98 min (>98%); MS (ESI) m/z=338.

8. 4-((3,4-difluorophenyl)ethynyl)benzoic acid

To a solution of ethyl 4-iodobenzoate (5.0 g, 18.1 mmol) in DMF (15 mL)was added 3,4-difluorophenylacetylene (2.99 g, 21.7 mmol), Pd(Ph₃P)₄(520 mg, 0.45 mmol), CuI (173 mg, 0.90 mmol) and diethylamine (3 mL).The reaction vessel was sealed and heated at 60° C. for 1 h in amicrowave reactor. The reaction was cooled to room temperature, dilutedwith EtOAc:hexanes (2:1, 150 mL) and washed with water (2×100 mL) andbrine (100 mL). The organic phase was dried over MgSO₄, filtered andconcentrated under vacuum. The crude product was dissolved in THF (60mL) added MeOH (14 mL) and a solution of LiOH (1.52 g, 36.2 mmol) inwater (14 mL). The reaction was stirred at room temperature and for 4 h.The reaction was acidified with 1 N HCl (60 mL) and4-((3,4-difluorophenyl)ethynyl)benzoic acid was isolated (2.45 g, 57%)as a white solid; ¹H-nmr (400 MHz, d₆-DMSO) δ 7.96 (d, J=8.5 Hz, 2H),7.73 (td, J=8.5, 2.0 Hz, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.55-7.43 (m, 2H);LC (290 nM) 5.08 min (>98%); MS (ESI) m/z=258.7.

9. (4-((3,4-difluorophenyl)ethynyl)phenyl)(morpholino)methanone

To a solution of acid 7 (2.40 g, 9.30 mmol) and DIPEA (3.34 g, 18.6mmol) in DMF (35 mL) was added EDC (2.07 g, 11.2 mmol), HOBt (1.25 g,9.3 mmol) and morpholine (1.04 g, 12.1 mmol). The reaction was stirredat room temperature for 18 h. The reaction was diluted with water (100mL) and (4-((3,4-difluorophenyl)ethynyl)phenyl)(morpholino)methanone wasisolated (2.91 g, 96%) as a white solid by vacuum filtration; ¹H-nmr(400 MHz, CDCl₃) δ 7.56 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.35(t, J=8.0 Hz, 1H), 7.31-7.25 (m, 1H), 7.15 (dd, J=18.0, 8.0 Hz, 1H),4.00-3.31 (bd s, 8H); LC (290 nM) 5.10 min (>98%); MS (ESI) m/z=327.9.

10. methyl 4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzoate

To a suspension of mono-methyl terephthalate (1.50 g, 8.33 mmol) inacetonitrile (16 mL) was added EDC (4.65 g, 25.0 mmol), HOBt (1.12 g,8.33 mmol), DIPEA (3.24 g, 25.0 mmol) and N-hydroxybenzimidamide (1.36g, 10.0 mmol). The reaction was heated at 100° C. for 30 mins in amicrowave. The reaction was then cooled to rt, diluted with water (60mL) and isolated the crude white precipitate by vacuum filtration.Dissolved in CH₂Cl₂ and passed through a plug of silica to afford methyl4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzoate as an off-white solid (640 mg,23%). ¹H-nmr (400 MHz, CDCl₃) δ 8.33 (d, J=8 Hz, 2H), 8.24 (d, J=8 Hz,2H), 8.21-8.11 (m, 2H), 7.59-7.51 (m, 3H), 4.00 (s, 3H); MS (ESI) m/z280.9

11. 4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzoic acid

To a solution of methyl 4-(3-(4-fluorophenyl)1,2,4-oxadiazol-5-yl)benzoate (600 mg, 2.14 mmol) in THF (12 mL) wasadded MeOH (3 mL) and a solution of LiOH (351 mg, 8.57 mmol) in H₂O (3mL). The reaction was stirred at room temperature for 2 h. The reactionwas quenched upon the addition of 1N HCl (30 mL) and extracted withEtOAc (2×30 mL). The organic extracts were dried over MgSO₄, andconcentrated under vacuum to afford4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzoic acid (550 mg, 87%) as a whitesolid. ¹H-nmr (400 MHz, CDCl₃) δ 8.37 (d, J=8 Hz, 2H), 8.30 (d, J=8 Hz,2H), 8.26-8.19 (m, 2H), 7.62-7.52 (m, 3H); MS (ESI) m/z 266.8

12. N-(3,3-dimethylbutyl)-4-(3-phenyl-1,2,4-oxadiazol-5-yl-benzamide

To a solution of 4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzoic acid (200 mg,0.75 mmol) in DMF (2 mL) was added EDC (167 mg, 0.90 mmol), HOBt (122mg, 0.90 mmol), DIPEA (200 mg, 1.50 mmol) and 3,3-dimethylbutylamine(113 mg, 1.12 mmol). The reaction was stirred at room temperature for 18h. The reaction was diluted with water (10 mL) and isolated the whiteprecipitate by vacuum filtration to affordN-(3,3-dimethylbutyl)-4-(3-phenyl-1,2,4-oxadiazol-5-yl-benzamide (248mg, 95%). ¹H-nmr (400 MHz, CDCl₃) δ 8.31 (d, J=8 Hz, 2H), 8.23-8.17 (m,2H), 7.95 (d, J=8 Hz, 2H), 7.59-7.52 (m, 3H), 6.12 (s, 1H), 3.57-3.51(m, 2H) 1.62-1.58 (m, 2H), 1.02 (s, 9H); MS (ESI) m/z 349.9.

13. (E)-ethyl 4-styrylbenzoate

To a solution of ethyl 4-iodobenzoate (1.0 g, 3.6 mmol) in DMF (4 mL)was added commercial (E)-styrylboronic acid (538 mg, 3.6 mmol) andcatalytic Pd(tBuP)₂. The reaction vessel was sealed and heated at 160°C. for 10 minutes in a microwave reactor. The reaction was cooled to rt,diluted with EtOAc:hexanes (2:1, 20 mL) and washed with water (2×20 mL)and brine (20 mL). The organic phase was dried over MgSO₄, filtered andconcentrated under vacuum. The crude product was purified by columnchromatography (silica gel) using 0 to 10% EtOAc/hexanes to afford(E)-ethyl 4-styrylbenzoate (771 mg, 85%) as a pale yellow solid; ¹H-nmr(400 MHz, CDCl₃) δ 8.05 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.56(dd, J=8.0, 2.0 Hz, 2H), 7.41-7.37 (m, 3H), 6.95 (d, 1H), 6.89 (d, 1H),4.41 (q, J=7.0 Hz, 2H), 1.44 (t, J=6.8 Hz, 3H); LCMS (214 nM) 3.58 min(>98%); MS (ESI) m/z=253.1.

14. (E)-ethyl 4-styrylbenzoic acid

To a solution of ester (E)-ethyl 4-styrylbenzoate (600 mg, 2.3 mmol) inTHF (5 mL) was added MeOH (2 mL) and a solution of LiOH (360 mg, 10mmol) in water (25 mL). The reaction was stirred at room temperature andfor 4 h. The reaction was acidified with 1 N HCl (10 mL) and isolated(E)-ethyl 4-styrylbenzoic acid (440 mg, 83%) as a white solid; ¹H-nmr(400 MHz, CDCl₃) δ 8.11 (d, J=8.0 Hz, 2H), 7.75-7.68 (m, 1H), 7.64 (d,J=8.0 Hz, 2H), 7.62-7.56 (m, 2H), 7.52-7.47 (m, 1H), 7.43-7.36 (m, 3H),6.97 (d, 1H), 6.88 (d, 1H); LCMS (214 nM) 3.22 min (>98%); MS (ESI)m/z=225.1.

15. (4-hydroxypiperidin-1-yl)(4-styrylphenyl)methanone

To a solution of (E)-ethyl 4-styrylbenzoic acid (300 mg, 1.3 mmol) andDIPEA (270 uL, 2.1 mmol) in DMF (5 mL) was added EDC (280 mg, 1.5 mmol),HOBt (270 mg, 2.0 mmol) and 4-hydroxypiperidine hydrochloride (258 mg,1.8 mmol). The reaction was stirred at room temperature for 18 h. Thereaction was diluted with water (10 mL) and(4-hydroxypiperidin-1-yl)(4-styrylphenyl)methanone was isolated (390 mg,98%) as a white solid by vacuum filtration; ¹H-nmr (400 MHz, CDCl₃) δ7.58 (d, J=8.0 Hz, 2H), 7.56-7.52 (m, 2H), 7.44-7.34 (m, 5H), 6.95 (d,1H), 6.89 (d, 1H), 4.21-4.08 (m, 1H), 4.03-3.96 (m, 1H), 3.81-3.48 (m,1H), 3.47-3.16 (m, 2H), 2.08-1.79 (m, 2H), 1.71-1.42 (m, 2H); LCMS (214nM) 3.32 min (>98%); MS (ESI) m/z=308.1.

16. methyl 4-(4-fluorophenylcarbamoyl)benzoate

To a suspension of mono-methyl terephthalate (2.0 g, 11.1 mmol) in DMF(10 mL) was added EDC (2.48 g, 13.3 mmol), HOBt (1.80 g, 13.3 mmol), and4-fluoroaniline (1.48 g, 13.3 mmol). The reaction was stirred at roomtemperature for 72 h. The reaction was diluted with water (80 mL) andisolated methyl 4-(4-fluorophenylcarbamoyl)benzoate (3.00 g, 98%) as awhite precipitate by vacuum filtration. ¹H-nmr (400 MHz, CDCl₃) δ 8.18(d, J=8 Hz, 2H), 7.95 (d, J=8 Hz, 2H), 7.82 (br s, 1H), 7.66-7.59 (m,2H), 7.15-7.07 (m, 2H), 3.99 (s, 3H); MS (ESI) m/z 273.9.

17. 4-(4-fluorophenylcarbamoyl)benzoic acid

To a solution of methyl 4-(4-fluorophenylcarbamoyl)benzoate (2.98 g,10.9 mmol) in THF (35 mL) was added MeOH (8 mL) and a solution of LiOH(1.79 g, 43.6 mmol) in H₂O (8 mL). The reaction was stirred at roomtemperature for 2 h. The reaction was quenched upon the addition of 1NHCl (50 mL) and extracted with EtOAc (2×60 mL). The organic extractswere dried over MgSO₄, and concentrated under vacuum to afford4-(4-fluorophenylcarbamoyl)benzoic acid (2.43 g, 86%) as a white solid.¹H-nmr (400 MHz, d₆-DMSO) δ 10.49 (s, 1H), 8.11-8.02 (m, 4H), 7.87-7.77(m, 2H), 7.25-7.16 (m, 2H); MS (ESI) m/z 259.9.

18. N-(4-fluorophenyl)-4-(2-methylpiperidine-1-carbonyl)benzamide

To a solution of 4-(4-fluorophenylcarbamoyl)benzoic acid (50 mg, 0.19mmol) in DMF (1 mL) was added PS-Carbodiimide (125 mg, 0.25 mmol), HOBt(26 mg, 0.19 mmol), DIPEA (52 mg, 0.40 mmol) and 2-methylpiperidine (25mg, 0.25 mmol). The reaction was agitated at room temperature for 18 h.To the reaction was added MP-carbonate and agitated for a further 8 h.The reaction was filtered and concentrated under vacuum to afforddiluted with water (10 mL) and isolated the white precipitate by vacuumfiltration to affordN-(4-fluorophenyl)-4-(2-methylpiperidine-1-carbonyl)benzamide (248 mg,95%). ¹H-nmr (400 MHz, d₆-DMSO) δ 10.37 (br s, 1H), 8.00 (d, J=7 Hz,2H), 7.83-7.72 (m, 2H), 7.49 (d, J=7 Hz, 2H), 7.21 (t, J=8 Hz, 2H),3.52-3.01 (m, 3H), 1.75-1.29 (m, 6H), 1.21 (m, 3H); MS (ESI) m/z 341.4.

19. In Vitro Studies

Human embryonic kidney (HEK) cells transfected with rat mGluR5 wereplated in clear-bottomed, poly-D-lysine-coated assay plates inglutamate-glutamine-free medium growth and incubated overnight at 37° C.in 5% CO₂. The following day, cells were loaded with 2 μM calciumindicator dye, fluo-4 AM, for 1 h at 37° C. Dye was removed and replacedwith assay buffer containing 1× Hanks balanced salt solution(Invitrogen, Carlsbad, Calif.), 20 mM HEPES, and 2.5 mM probenecid, pH7.4. Cell plates were then loaded into the Functional Drug ScreeningSystem 6000 (FDSS 6000, Hamamatsu, Japan). After establishment of afluorescence baseline for twelve seconds, the compounds of the presentinvention were added to the cells, and the response in cells wasmeasured. Five minutes later, an mGluR5 agonist (e.g., glutamate,3,5-dihydroxyphenylglycine, or quisqualate) was added to the cells, andthe response of the cells was measured during a 1 minute incubation withagonists. Typically, the effect of test compounds of the presentinvention was on an EC₂₀ concentration of glutamate was measured. Alltest compounds were dissolved and diluted in 100% DMSO and then seriallydiluted into assay buffer for a 2.5× stock in 0.25% DMSO; stockcompounds were then added to the assay for a final DMSO concentration of0.1%. Calcium fluorescence measures were recorded as fold over basalfluorescence; raw data was then normalized to the maximal response toagonist. Potentiation of the agonist response of mGluR5 by the compoundsin the present invention was observed as an increase in response tonon-maximal concentrations of agonist (here, glutamate) in the presenceof compound compared to the response to agonist in the absence ofcompound.

20. Behavior Evaluation

Locomotor activity can be assessed as mean distance traveled (cm) instandard 16×16 photocell testing chambers measuring 43.2 cm (L)×43.2 cm(W)×30.5 cm (H) (Med Associates, St. Albans, Vt.). Animals can behabituated to individual activity chambers for at least 60 min prior todrug administration. Following administration of appropriate drugs orvehicle, activity can be recorded for a 3 hr time period. Data can beexpressed as the mean (±SEM) distance traveled recorded in 10 minintervals over the test period. The data can be analyzed using repeatedmeasures analysis of variance (ANOVA) followed by post-hoc testing usingTukey's HSD test, when appropriate. A difference can be consideredsignificant when p≦0.05.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

What is claimed is:
 1. A compound having a structure represented by aformula:

wherein N, R¹, and R² together form an optionally substitutedheterocyclic ring having from two to seven carbons; wherein both of Y¹and Y² are carbon; wherein R represents four substituents independentlyselected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or anorganic radical comprising 1 to 12 carbon atoms; wherein all of Z¹, Z²,and Z³ are carbon; and wherein R⁴ represents five substituentsindependently selected from hydrogen, halogen, and cyano, wherein atleast one of R⁴ is halogen selected from F and Cl; or a pharmaceuticallyacceptable salt or N-oxide thereof, wherein the compound exhibitspotentiation of mGluR5 response to glutamate as an increase in responseto non-maximal concentrations of glutamate in human embryonic kidneycells transfected with rat mGluR5 in the presence of the compound,compared to the response to glutamate in the absence of the compound. 2.The compound of claim 1, wherein R represents four substituentsindependently selected from hydrogen, halogen, and lower alkyl.
 3. Thecompound of claim 1, wherein N, R¹, and R² together form a cyclicoptionally substituted alkyl residue selected from(E)-4-hydroxypiperidin-1-yl;(S)-(4-(1-cyclohexylethylamino)piperidin-1-yl;1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one;1-(piperidin-4-yl)ethanone; 2-(piperazin-1-yl)benzonitrile;2,6-dimethylmorpholino; 2-morpholinoethyl;3-hydroxy-3-(thiophen-2-yl)azetidin-1-yl;3-hydroxy-3-methylazetidin-1-yl; 3-hydroxy-3-propylazetidin-1-yl;3-hydroxyazetidin-1-yl; 3-hydroxypiperidin-1-yl;4-(2-fluorophenyl)piperazin-1-yl; 4-(2-methoxyethylamino)piperidin-1-yl;4-(2-methoxyphenyl)piperazin-1-yl;4-(2-morpholinoethylamino)piperidin-1-yl;4-(3-fluorophenyl)-4-hydroxypiperidin-1-yl;4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-1-yl;4-(4-bromophenyl)-4-hydroxypiperidin-1-yl;4-(4-chloro-2-(trifluoromethyl)phenyl)-4-hydroxypiperidin-1-yl;4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl;4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl;4-(4-methylpiperazin-1-yl)piperidin-1-yl;4-(azetidin-1-yl)piperidin-1-yl; 4-(cyclobutylamino)piperidin-1-yl;4-(cyclopropylmethylamino)piperidin-1-yl;4-(hydroxymethyl)piperidin-1-yl; 4-(pyridin-2-yl)piperazin-1-yl;4-(pyrrolidin-1-yl)piperidin-1-yl;4-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl;4-hydroxy-4-(thiophen-2-yl)piperidin-1-yl;4-hydroxy-4-isopropylpiperidin-1-yl; 4-hydroxy-4-methylpiperidin-1-yl;4-hydroxypiperidin-1-yl; 4-isopropylpiperazin-1-yl;4-methylpiperazin-1-yl; 4-phenyl-1-piperidine-4-carbonitrile;6-chloro-1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one; morpholino;octahydroisoquinolin-2(1H)-yl; and piperazin-1-yl.
 4. The compound ofclaim 1, wherein the compound exhibits potentiation of mGluR5 responseto glutamate with an EC₅₀ of less than 1.0×10⁻⁶.
 5. The compound ofclaim 1, wherein the compound exhibits potentiation of mGluR5 responseto glutamate with an EC₅₀ of less than 1.0×10⁻⁷.
 6. The compound ofclaim 1, wherein the compound exhibits potentiation of mGluR5 responseto glutamate with an EC₅₀ of less than 1.0×10⁻⁸.
 7. The compound ofclaim 1, wherein R represents four hydrogens.
 8. The compound of claim1, having a structure represented by a formula:


9. A compound having a structure represented by a formula: